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1
Böckler, Stefan, and Benedikt Westermann. "ER-mitochondria contacts as sites of mitophagosome formation." Autophagy 10, no. 7 (May 15, 2014): 1346–47. http://dx.doi.org/10.4161/auto.28981.
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Ng, Amanda Yunn Ee, Annabel Qi En Ng, and Dan Zhang. "ER-PM Contacts Restrict Exocytic Sites for Polarized Morphogenesis." Current Biology 28, no. 1 (January 2018): 146–53. http://dx.doi.org/10.1016/j.cub.2017.11.055.
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Chandiwana, S. K., and M. E. J. Woolhouse. "Heterogeneities in water contact patterns and the epidemiology of schistosoma haematobium." Parasitology 103, no. 3 (December 1991): 363–70. http://dx.doi.org/10.1017/s0031182000059874.
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Variations in the amount of water contact made by individuals and in the amount of water contact made at different sites may have significant impacts on patterns of human schistosome infection. Previous studies have reported variations in the rate of water contact and differences in the sites used between age/sex classes, but there is limited information on variations in individual water contact behaviour. In this paper we report and analyse observations of essentially all water contacts made over a two week period by all individuals in a rural community in eastern Zimbabwe. The mean rate of water contact was 0.43 contacts/person/day. These data were over-dispersed, ranging from zero to 3.3 contacts/person/day; 90% of contacts were made by only 37% of the population. Contact rates were related to age (highest in 8 to 10-year-olds) but not sex, with substantial variation unaccounted for by these variables. Age and sex classes differed in types of water-related activities and the time of day of contact. A greater diversity of sites was used by children than by adults and by males than by females. Individual contact rates were correlated with intensities of infection, although the risk of infection per contact was estimated to be highest in 2 to 4-year-old children and higher for males than females. Five contact sites were used during the study period, with more than 50% of contacts occurring at just 2 sites. Different age and sex classes used different sites and there were additional site-related differences in types of activity and the time of day of use. The implications of these water contact patterns for schistosome epidemiology are discussed. In particular the results provide strong quantitative support for control programmes aimed at heavily used sites (e.g. focal mollusciciding) or at the minority of individuals making most water contacts (e.g. targeted chemotherapy).
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Fernández-Busnadiego, Rubén, Yasunori Saheki, and Pietro De Camilli. "Three-dimensional architecture of extended synaptotagmin-mediated endoplasmic reticulum–plasma membrane contact sites." Proceedings of the National Academy of Sciences 112, no. 16 (March 18, 2015): E2004—E2013. http://dx.doi.org/10.1073/pnas.1503191112.
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The close apposition between the endoplasmic reticulum (ER) and the plasma membrane (PM) plays important roles in Ca2+ homeostasis, signaling, and lipid metabolism. The extended synaptotagmins (E-Syts; tricalbins in yeast) are ER-anchored proteins that mediate the tethering of the ER to the PM and are thought to mediate lipid transfer between the two membranes. E-Syt cytoplasmic domains comprise a synaptotagmin-like mitochondrial-lipid–binding protein (SMP) domain followed by five C2 domains in E-Syt1 and three C2 domains in E-Syt2/3. Here, we used cryo-electron tomography to study the 3D architecture of E-Syt–mediated ER–PM contacts at molecular resolution. In vitrified frozen-hydrated mammalian cells overexpressing individual E-Syts, in which E-Syt–dependent contacts were by far the predominant contacts, ER–PM distance (19–22 nm) correlated with the amino acid length of the cytosolic region of E-Syts (i.e., the number of C2 domains). Elevation of cytosolic Ca2+ shortened the ER–PM distance at E-Syt1–dependent contacts sites. E-Syt–mediated contacts displayed a characteristic electron-dense layer between the ER and the PM. These features were strikingly different from those observed in cells exposed to conditions that induce contacts mediated by the stromal interaction molecule 1 (STIM1) and the Ca2+ channel Orai1 as well as store operated Ca2+ entry. In these cells the gap between the ER and the PM was spanned by filamentous structures perpendicular to the membranes. Our results define specific ultrastructural features of E-Syt–dependent ER–PM contacts and reveal their structural plasticity, which may impact on the cross-talk between the ER and the PM and the functions of E-Syts in lipid transport between the two bilayers.
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Veerasamy, N., and W. A. Labuschagne. "Ascertaining Trust Indicators in Social Networking Sites." International Journal of Cyber Warfare and Terrorism 3, no. 2 (April 2013): 22–37. http://dx.doi.org/10.4018/ijcwt.2013040102.
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The use of social network sites has exploded with its multitude of functions which include posting pictures, interests, activities and establishing contacts. However, users may be unaware of the lurking dangers of threats originating from Social Networking Sites (SNS) which include malware or fake profiles. This paper investigates the indicators to arouse suspicion that a social networking account is invalid with a specific focus on Facebook as an illustrative example. The results from a survey on users’ opinions on social networks, is presented in the paper. This helps reveal some of the trust indicators that leads users to ascertaining whether a social networking profile is valid or not. Finally, indicators of potentially deceptive agents and profiles are given as a guideline to help users decide whether they should proceed with interaction with certain contacts.
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O'Reilly, Andrias O., Bhupinder P. S. Khambay, Martin S. Williamson, Linda M. Field, B. A. WAllace, and T. G. Emyr Davies. "Modelling insecticide-binding sites in the voltage-gated sodium channel." Biochemical Journal 396, no. 2 (May 15, 2006): 255–63. http://dx.doi.org/10.1042/bj20051925.
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A homology model of the housefly voltage-gated sodium channel was developed to predict the location of binding sites for the insecticides fenvalerate, a synthetic pyrethroid, and DDT an early generation organochlorine. The model successfully addresses the state-dependent affinity of pyrethroid insecticides, their mechanism of action and the role of mutations in the channel that are known to confer insecticide resistance. The sodium channel was modelled in an open conformation with the insecticide-binding site located in a hydrophobic cavity delimited by the domain II S4-S5 linker and the IIS5 and IIIS6 helices. The binding cavity is predicted to be accessible to the lipid bilayer and therefore to lipid-soluble insecticides. The binding of insecticides and the consequent formation of binding contacts across different channel elements could stabilize the channel when in an open state, which is consistent with the prolonged sodium tail currents induced by pyrethroids and DDT. In the closed state, the predicted alternative positioning of the domain II S4-S5 linker would result in disruption of pyrethroid-binding contacts, consistent with the observation that pyrethroids have their highest affinity for the open channel. The model also predicts a key role for the IIS5 and IIIS6 helices in insecticide binding. Some of the residues on the helices that form the putative binding contacts are not conserved between arthropod and non-arthropod species, which is consistent with their contribution to insecticide species selectivity. Additional binding contacts on the II S4-S5 linker can explain the higher potency of pyrethroid insecticides compared with DDT.
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Bloch, R. J. "Clusters of neural cell adhesion molecule at sites of cell-cell contact." Journal of Cell Biology 116, no. 2 (January 15, 1992): 449–63. http://dx.doi.org/10.1083/jcb.116.2.449.
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I have examined the distribution of neural cell adhesion molecule (N-CAM) in cultured C2 myogenic cells and other cell lines to determine if N-CAM accumulates at sites of cell-cell contact. C2 cells growing in log phase display large clusters of neural cell adhesion molecule where they contact each other. These clusters are remarkably stable, do not form at cell-substrate contacts, and appear not to be enriched in a number of other cytoskeletal, membrane, or extracellular proteins. Thus, N-CAM clusters form preferentially in response to cell-cell contact and are specifically enriched in N-CAM. As C2 cultures mature and differentiate, clusters persist at contacts between aligning myoblasts and between myotubes, consistent with a role in myogenesis. N-CAM is also enriched at cell-cell contacts in cultures of PC12, NRK, and CHO cells. These cells have significant amounts of N-CAM as detected on immunoblots. Clusters are not seen in L929 cells, which do not have detectable amounts of N-CAM. Coculture of these cells with C2 cells results in the clustering of N-CAM at heterologous contacts between C2 cells and NRK, CHO, or PC12 cells, but not between C2 cells and L929 cells. These results suggest that N-CAM specifically accumulates where N-CAM-bearing cells contact one another. Clustering of N-CAM may be an important step in strengthening intercellular adhesion.
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Singer, I. I., S. Scott, D. W. Kawka, D. M. Kazazis, J. Gailit, and E. Ruoslahti. "Cell surface distribution of fibronectin and vitronectin receptors depends on substrate composition and extracellular matrix accumulation." Journal of Cell Biology 106, no. 6 (June 1, 1988): 2171–82. http://dx.doi.org/10.1083/jcb.106.6.2171.
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We used antibodies against the alpha subunits of the human fibronectin receptor (FNR) and vitronectin receptor (VNR) to localize simultaneously FNR and VNR at major substrate adhesion sites of fibroblasts and melanoma cells with double-label immunofluorescence microscopy. In early (2-6-h) serum-containing cultures, both FNR and VNR coaccumulated in focal contacts detected by interference reflection microscopy. Under higher resolution immunoscanning electron microscopy, FNR and VNR were also observed to be distributed randomly on the dorsal cell surface. As fibronectin-containing extracellular matrix fibers accumulated beneath the cells at 24 h, FNR became concentrated at contacts with these fibers and was no longer detected at focal contacts. VNR was not observed at matrix contacts but remained strikingly localized in focal contacts of the 24-h cells. Since focal contacts represent the sites of strongest cell-to-substrate adhesion, these results suggest that FNR and VNR together play critical roles in the maintenance of stable contacts between the cell and its substrate. In addition, the accumulation of FNR at extracellular matrix contacts implies that this receptor might also function in the process of cellular migration along fibronectin-containing matrix cables. To define the factors governing accumulation of FNR and VNR at focal contacts, fibroblasts in serum-free media were plated on substrates coated with purified ligands. Fibronectin-coated surfaces fostered accumulation of FNR but not VNR at focal contacts. On vitronectin-coated surfaces, or substrata derivatized with a tridecapeptide containing the cell attachment sequence Arg-Gly-Asp, both FNR and VNR became concentrated at focal contacts. These observations suggest that the availability of ligand is critical to the accumulation of FNR and VNR at focal contacts, and that FNR might also recognize substrate-bound vitronectin.
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Rinnerthaler, G., B. Geiger, and J. V. Small. "Contact formation during fibroblast locomotion: involvement of membrane ruffles and microtubules." Journal of Cell Biology 106, no. 3 (March 1, 1988): 747–60. http://dx.doi.org/10.1083/jcb.106.3.747.
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We have correlated the motility of the leading edge of fibroblasts, monitored by phase-contrast cinematography, with the relative distributions of several cytoskeletal elements (vinculin, tubulin, and actin) as well as with the contact patterns determined by interference reflection microscopy. This analysis has revealed the involvement of both ruffles and microspikes, as well as microtubules in the initiation of focal contact formation. Nascent vinculin sites within the leading edge or at its base, taken as primordial cell-substrate contacts, were invariably colocalized with sites that showed a history of transient, prolonged, or cyclic ruffling activity. Extended microspike structures, often preceded the formation of ruffles. Immunofluorescent labeling indicated that some of these primordial contacts were in close apposition to the ends of microtubules that penetrated into the leading edge. By fluorescence and electron microscopy short bundles of actin filaments found at the base of the leading edge were identified as presumptive, primordial contacts. It is concluded that ruffles and microspikes, either independently or in combination, initiate and mark the sites for future contact. Plaque proteins then accumulate (within 10-30 s) at the contract site and, beneath ruffles, induce localized bundling of actin filaments. We propose that all primordial contacts support traction for leading edge protrusion but that only some persist long enough to nucleate stress fiber assembly. Microtubules are postulated as the elements that select, stabilize, and potentiate the formation of these latter, long-lived contacts.
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Wong, Louise H., and Tim P. Levine. "Lipid transfer proteins do their thing anchored at membrane contact sites… but what is their thing?" Biochemical Society Transactions 44, no. 2 (April 11, 2016): 517–27. http://dx.doi.org/10.1042/bst20150275.
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Membrane contact sites are structures where two organelles come close together to regulate flow of material and information between them. One type of inter-organelle communication is lipid exchange, which must occur for membrane maintenance and in response to environmental and cellular stimuli. Soluble lipid transfer proteins have been extensively studied, but additional families of transfer proteins have been identified that are anchored into membranes by transmembrane helices so that they cannot diffuse through the cytosol to deliver lipids. If such proteins target membrane contact sites they may be major players in lipid metabolism. The eukaryotic family of so-called Lipid transfer proteins Anchored at Membrane contact sites (LAMs) all contain both a sterol-specific lipid transfer domain in the StARkin superfamily (related to StART/Bet_v1), and one or more transmembrane helices anchoring them in the endoplasmic reticulum (ER), making them interesting subjects for study in relation to sterol metabolism. They target a variety of membrane contact sites, including newly described contacts between organelles that were already known to make contact by other means. Lam1–4p target punctate ER–plasma membrane contacts. Lam5p and Lam6p target multiple contacts including a new category: vacuolar non-NVJ cytoplasmic ER (VancE) contacts. These developments confirm previous observations on tubular lipid-binding proteins (TULIPs) that established the importance of membrane anchored proteins for lipid traffic. However, the question remaining to be solved is the most difficult of all: are LAMs transporters, or alternately are they regulators that affect traffic more indirectly?
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Dunn, Tyler W., and Wayne S. Sossin. "Excitatory postsynaptic calcium transients at Aplysia sensory–motor neuron synapses allow for quantal examination of synaptic strength over multiple days in culture." Learning & Memory 28, no. 9 (August 16, 2021): 277–90. http://dx.doi.org/10.1101/lm.052639.120.
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A more thorough description of the changes in synaptic strength underlying synaptic plasticity may be achieved with quantal resolution measurements at individual synaptic sites. Here, we demonstrate that by using a membrane targeted genetic calcium sensor, we can measure quantal synaptic events at the individual synaptic sites of Aplysia sensory neuron to motor neuron synaptic connections. These results show that synaptic strength is not evenly distributed between all contacts in these cultures, but dominated by multiquantal sites of synaptic contact, likely clusters of individual synaptic sites. Surprisingly, most synaptic contacts were not found opposite presynaptic varicosities, but instead at areas of pre- and postsynaptic contact with no visible thickening of membranes. The release probability, quantal size, and quantal content can be measured over days at individual synaptic contacts using this technique. Homosynaptic depression was accompanied by a reduction in release site probability, with no evidence of individual synaptic site silencing over the course of depression. This technique shows promise in being able to address outstanding questions in this system, including determining the synaptic changes that maintain long-term alterations in synaptic strength that underlie memory.
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Ballestrem, Christoph, Boris Hinz, Beat A. Imhof, and Bernhard Wehrle-Haller. "Marching at the front and dragging behind." Journal of Cell Biology 155, no. 7 (December 24, 2001): 1319–32. http://dx.doi.org/10.1083/jcb.200107107.
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Integrins are cell–substrate adhesion molecules that provide the essential link between the actin cytoskeleton and the extracellular matrix during cell migration. We have analyzed αVβ3-integrin dynamics in migrating cells using a green fluorescent protein–tagged β3-integrin chain. At the cell front, adhesion sites containing αVβ3-integrin remain stationary, whereas at the rear of the cell they slide inward. The integrin fluorescence intensity within these different focal adhesions, and hence the relative integrin density, is directly related to their mobility. Integrin density is as much as threefold higher in sliding compared with stationary focal adhesions. High intracellular tension under the control of RhoA induced the formation of high-density contacts. Low-density adhesion sites were induced by Rac1 and low intracellular tension. Photobleaching experiments demonstrated a slow turnover of β3-integrins in low-density contacts, which may account for their stationary nature. In contrast, the fast β3-integrin turnover observed in high-density contacts suggests that their apparent sliding may be caused by a polarized renewal of focal contacts. Therefore, differential acto-myosin–dependent integrin turnover and focal adhesion densities may explain the mechanical and behavioral differences between cell adhesion sites formed at the front, and those that move in the retracting rear of migrating cells.
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Zammar, Nisrine. "Social Network Sites." International Journal of Actor-Network Theory and Technological Innovation 2, no. 2 (April 2010): 54–62. http://dx.doi.org/10.4018/jantti.2010040104.
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This article examines the role of actors in a Social Network Sites and also the triggers and challenges they represent to social networking between today’s communities and businesses. A Social Network Sites is the product of the evolution of social liaisons and the emergence of online communities of people who are interested in exploring the concerns and activities of others. A social network is the assembly of direct or indirect contacts; a network is the product of interactions with the actors (individuals, families, enterprises, etc.) enabled by means of the structural design of web 2.0. Social Network Sites bring people together to interact through chat rooms, and share personal information and ideas around any topics via personal homepage publishing tools. This article is intended to be a trigger to deeply and more intensely explore potential roles of actor-network theory in the Social Network Sites context, in today’s and tomorrow’s world.
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WOOLHOUSE, M. E. J., J. F. ETARD, K. DIETZ, P. D. NDHLOVU, and S. K. CHANDIWANA. "Heterogeneities in schistosome transmission dynamics and control." Parasitology 117, no. 5 (November 1998): 475–82. http://dx.doi.org/10.1017/s003118209800331x.
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We review the theoretical framework for exploring the impact of individual and spatial heterogeneities in patterns of exposure and contamination and on the basic reproduction number, R0, for human schistosomes. Analysis of water contact data for 5 communities in Zimbabwe and Mali suggests that the impact is substantial, increasing R0 by factors of up to 6·5, mostly due to highly overdispersed distributions of contact rates among individuals. Several practical conclusions emerge: concentration of contacts at a single site should be avoided; the impact of control targeted at certain sites cannot be predicted without knowledge of how individuals' contacts are distributed among sites; control programmes targeted at individuals or sites contributing most to transmission can be very efficient but, conversely, will be ineffective if any of these individuals or sites are missed.
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Garcia-Garcia, David, Jorge Guridi, Jon B. Toledo, Manuel Alegre, José A. Obeso, and María C. Rodríguez-Oroz. "Stimulation sites in the subthalamic nucleus and clinical improvement in Parkinson's disease: a new approach for active contact localization." Journal of Neurosurgery 125, no. 5 (November 2016): 1068–79. http://dx.doi.org/10.3171/2015.9.jns15868.
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OBJECTIVE Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is widely used in patients with Parkinson's disease (PD). However, which target area of this region results in the highest antiparkinsonian efficacy is still a matter of debate. The aim of this study was to develop a more accurate methodology to locate the electrodes and the contacts used for chronic stimulation (active contacts) in the subthalamic region, and to determine the position at which stimulation conveys the greatest clinical benefit. METHODS The study group comprised 40 patients with PD in whom bilateral DBS electrodes had been implanted in the STN. Based on the Morel atlas, the authors created an adaptable 3D atlas that takes into account individual anatomical variability and divides the STN into functional territories. The locations of the electrodes and active contacts were obtained from an accurate volumetric assessment of the artifact using preoperative and postoperative MR images. Active contacts were positioned in the 3D atlas using stereotactic coordinates and a new volumetric method based on an ellipsoid representation created from all voxels that belong to a set of contacts. The antiparkinsonian benefit of the stimulation was evaluated by the reduction in the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) score and in the levodopa equivalent daily dose (LEDD) at 6 months. A homogeneous group classification for contact position and the respective clinical improvement was applied using a hierarchical clustering method. RESULTS Subthalamic stimulation induced a significant reduction of 58.0% ± 16.5% in the UPDRS-III score (p < 0.001) and 64.9% ± 21.0% in the LEDD (p < 0.001). The greatest reductions in the total and contralateral UPDRS-III scores (64% and 76%, respectively) and in the LEDD (73%) were obtained when the active contacts were placed approximately 12 mm lateral to the midline, with no influence of the position being observed in the anteroposterior and dorsoventral axes. In contrast, contacts located about 10 mm from the midline only reduced the global and contralateral UPDRS-III scores by 47% and 41%, respectively, and the LEDD by 33%. Using the ellipsoid method of location, active contacts with the highest benefit were positioned in the rostral and most lateral portion of the STN and at the interface between this subthalamic region, the zona incerta, and the thalamic fasciculus. Contacts placed in the most medial regions of the motor STN area provided the lowest clinical efficacy. CONCLUSIONS The authors report an accurate new methodology to assess the position of electrodes and contacts used for chronic subthalamic stimulation. Using this approach, the highest antiparkinsonian benefit is achieved when active contacts are located within the rostral and the most lateral parts of the motor region of the STN and at the interface of this region and adjacent areas (zona incerta and thalamic fasciculus).
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Stickel, S. K., and Y. L. Wang. "Synthetic peptide GRGDS induces dissociation of alpha-actinin and vinculin from the sites of focal contacts." Journal of Cell Biology 107, no. 3 (September 1, 1988): 1231–39. http://dx.doi.org/10.1083/jcb.107.3.1231.
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The synthetic peptide Gly-Arg-Gly-Asp-Ser (GRGDS) mimics the cellular binding site of many adhesive proteins in the extracellular matrix and causes rounding and detachment of spread cells. We have studied whether its binding affects the associations of two major components, alpha-actinin and vinculin, at the adhesion plaque. Living 3T3 cells were microinjected with fluorescently labeled alpha-actinin and/or vinculin and observed using video microscopy before and after the addition of 50 micrograms/ml GRGDS. As soon as 5 min after treatment, fluorescent alpha-actinin and vinculin became dissociated simultaneously from the sites of many focal contacts. The proteins either moved away as discrete structures or dispersed from adhesion plaques. As a result, the enrichment of alpha-actinin and vinculin at these focal contacts was no longer detected. The focal contacts then faded away slowly without showing detectable movement. These data suggest that the binding state of integrin has a transmembrane effect on the distribution of cytoskeletal components. The dissociation of alpha-actinin and vinculin from adhesion plaques may in turn weaken the contacts and result in rounding and detachment of cells.
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Chen, Jiaqi, Zhaofu Zhang, Yuzheng Guo, and John Robertson. "Metal contacts with Moire interfaces on WSe2 for ambipolar applications." Applied Physics Letters 121, no. 5 (August 1, 2022): 051602. http://dx.doi.org/10.1063/5.0091504.
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The rational design of metal contacts on transition metal dichalcogenides can significantly improve the performance of 2D devices. We have previously shown that a Moire interface between n-type monolayer MoS2 and metal contacts enhances the stability of physisorptive interface sites, thereby enabling weaker Fermi level pinning and allowing easier variation of the Schottky barrier height at these interfaces. We extend these calculations to p-type and ambipolar WSe2 contacts in this work. The analysis shows that the Moire interfaces again have a weaker Fermi level pinning, while most metals have chemisorptive sites with stronger pinning. We find that the most stable site of Pd is a Moire site with an unusually low p-type Schottky barrier height (p-SBH), while Au has a metastable low p-SBH. In and Al retain their low n-type SBHs, which together with Pd enable ambipolar contacts by the choice of contact metals, indicating that WSe2 can be used for high-performance ambipolar devices with the rational design of contact metals.
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Lu, Y., C. Flaherty, and W. Hendrickson. "AraC protein contacts asymmetric sites in the Escherichia coli araFGH promoter." Journal of Biological Chemistry 267, no. 34 (December 1992): 24848–57. http://dx.doi.org/10.1016/s0021-9258(18)35841-1.
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Erustes, Adolfo Garcia, Gabriel Cicolin Guarache, Erika da Cruz Guedes, Anderson Henrique França Figueredo Leão, Gustavo José da Silva Pereira, and Soraya Soubhi Smaili. "α-Synuclein Interactions in Mitochondria-ER Contacts: A Possible Role in Parkinson's Disease." Contact 5 (January 2022): 251525642211193. http://dx.doi.org/10.1177/25152564221119347.
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Endoplasmic reticulum-mitochondria contact sites regulate various biological processes, such as mitochondrial dynamics, calcium homeostasis, autophagy and lipid metabolism. Notably, dysfunctions in these contact sites are closely related to neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. However, details about the role of endoplasmic reticulum-mitochondria contact sites in neurodegenerative diseases remain unknown. In Parkinson's disease, interactions between α-synuclein in the contact sites and components of tether complexes that connect organelles can lead to various dysfunctions, especially with regards to calcium homeostasis. This review will summarize the main tether complexes present in endoplasmic reticulum-mitochondria contact sites, and their roles in calcium homeostasis and trafficking. We will discuss the impact of α-synuclein accumulation, its interaction with tethering complex components and the implications in Parkinson’s disease pathology.
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Bean, Björn D. M., Samantha K. Dziurdzik, Kathleen L. Kolehmainen, Claire M. S. Fowler, Waldan K. Kwong, Leslie I. Grad, Michael Davey, Cayetana Schluter, and Elizabeth Conibear. "Competitive organelle-specific adaptors recruit Vps13 to membrane contact sites." Journal of Cell Biology 217, no. 10 (July 17, 2018): 3593–607. http://dx.doi.org/10.1083/jcb.201804111.
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The regulated expansion of membrane contact sites, which mediate the nonvesicular exchange of lipids between organelles, requires the recruitment of additional contact site proteins. Yeast Vps13 dynamically localizes to membrane contacts that connect the ER, mitochondria, endosomes, and vacuoles and is recruited to the prospore membrane in meiosis, but its targeting mechanism is unclear. In this study, we identify the sorting nexin Ypt35 as a novel adaptor that recruits Vps13 to endosomal and vacuolar membranes. We characterize an interaction motif in the Ypt35 N terminus and identify related motifs in the prospore membrane adaptor Spo71 and the mitochondrial membrane protein Mcp1. We find that Mcp1 is a mitochondrial adaptor for Vps13, and the Vps13–Mcp1 interaction, but not Ypt35, is required when ER-mitochondria contacts are lost. All three adaptors compete for binding to a conserved six-repeat region of Vps13 implicated in human disease. Our results support a competition-based model for regulating Vps13 localization at cellular membranes.
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Yan, Qi, Nicolas Gaspard, Hitten P. Zaveri, Hal Blumenfeld, Lawrence J. Hirsch, Dennis D. Spencer, and Rafeed Alkawadri. "The connectivity index: an effective metric for grading epileptogenicity." Journal of Neurosurgery 133, no. 4 (October 2020): 971–78. http://dx.doi.org/10.3171/2019.4.jns195.
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OBJECTIVEThe aim of this study was to investigate the performance of a metric of functional connectivity to classify and grade the excitability of brain regions based on evoked potentials in response to single-pulse electrical stimulation (SPES).METHODSPatients who underwent 1-Hz frequency stimulation at prospectively selected contacts between 2003 and 2014 at the Yale Comprehensive Epilepsy Center were included. The stimulated contacts were classified as the seizure onset zone (SOZ), highly irritative zone (possibly epileptogenic irritative zone [IZp]), and control contacts not involved in the epileptic activity. Response contacts were classified as SOZ, active interictal irritative zone (IZ), quiet, or other. The normalized number of responses was defined as the number of contacts with any evoked responses divided by the total number of recorded contacts, and the normalized distance is the ratio of the average distance between the site of stimulation and sites of evoked responses to the average distances between the site of stimulation and all other recording contacts. A new metric that the authors labeled the connectivity index (CI) is defined as the product of the 2 values.RESULTSA total of 57 stimulation sessions in 22 patients were analyzed. The CI of the SOZ was higher than for control contacts (median CI of 0.74 vs 0.16, p = 0.0002). The evoked responses after stimulation of SOZ were seen at further distances compared to control (median normalized distance 0.96 vs 0.62, p = 0.0005). It was 1.8 times more likely that a response would be recorded at the SOZ than in nonepileptic contacts after stimulation of a control site. Habitual seizures were triggered in 27% of patients and 35% of SOZ contacts (median stimulation intensity 4 mA) but in none of the control or IZp contacts. Non-SOZ contacts in multifocal or poor surgical outcome cases had a higher CI than non-SOZ contacts in patients with localizable onsets (median CI of 0.5 vs 0.12, p = 0.04). There was a correlation between the stimulation current intensity and the normalized number of evoked responses (r = + 0.49, p = 0.01) but not with distance (r = + 0.1, p = 0.64).CONCLUSIONSThe authors found enhanced connectivity when stimulating the SOZ compared to stimulating control contacts; responses were more distant as well. Habitual auras and seizures provoked by SPES were highly predictive of brain sites involved in seizure generation.
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Gerardos, Andonis, Nicola Dietler, and Anne-Florence Bitbol. "Correlations from structure and phylogeny combine constructively in the inference of protein partners from sequences." PLOS Computational Biology 18, no. 5 (May 16, 2022): e1010147. http://dx.doi.org/10.1371/journal.pcbi.1010147.
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Inferring protein-protein interactions from sequences is an important task in computational biology. Recent methods based on Direct Coupling Analysis (DCA) or Mutual Information (MI) allow to find interaction partners among paralogs of two protein families. Does successful inference mainly rely on correlations from structural contacts or from phylogeny, or both? Do these two types of signal combine constructively or hinder each other? To address these questions, we generate and analyze synthetic data produced using a minimal model that allows us to control the amounts of structural constraints and phylogeny. We show that correlations from these two sources combine constructively to increase the performance of partner inference by DCA or MI. Furthermore, signal from phylogeny can rescue partner inference when signal from contacts becomes less informative, including in the realistic case where inter-protein contacts are restricted to a small subset of sites. We also demonstrate that DCA-inferred couplings between non-contact pairs of sites improve partner inference in the presence of strong phylogeny, while deteriorating it otherwise. Moreover, restricting to non-contact pairs of sites preserves inference performance in the presence of strong phylogeny. In a natural data set, as well as in realistic synthetic data based on it, we find that non-contact pairs of sites contribute positively to partner inference performance, and that restricting to them preserves performance, evidencing an important role of phylogeny.
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Sassano, Maria Livia, Rita Derua, Etienne Waelkens, Patrizia Agostinis, and Alexander R. van Vliet. "Interactome Analysis of the ER Stress Sensor Perk Uncovers Key Components of ER-Mitochondria Contact Sites and Ca2+ Signalling." Contact 4 (January 2021): 251525642110523. http://dx.doi.org/10.1177/25152564211052392.
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We recently reported that the ER stress kinase PERK regulates ER-mitochondria appositions and ER– plasma membrane (ER-PM) contact sites, independent of its canonical role in the unfolded protein response. PERK regulation of ER-PM contacts was revealed by a proximity biotinylation (BioID) approach and involved a dynamic PERK-Filamin A interaction supporting the formation of ER-PM contacts by actin-cytoskeleton remodeling in response to depletion of ER-Ca2+ stores. In this report, we further interrogated the PERK BioID interactome by validating through co-IP experiments the interaction between PERK and two proteins involved in Ca2+ handling and ER-mitochondria contact sites. These included the vesicle associated membrane (VAMP)-associated proteins (VAPA/B) and the main ER Ca2+ pump sarcoplasmic/endoplasmic reticulum Ca ATPase 2 (SERCA2). These data identify new putative PERK interacting proteins with a crucial role in membrane contact sites and Ca2+ signaling further supporting the uncanonical role of PERK in Ca2+ signaling through membrane contact sites (MCSs).
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Henne, W. Mike, and Hanaa Hariri. "Endoplasmic Reticulum-Vacuole Contact Sites “Bloom” With Stress-Induced Lipid Droplets." Contact 1 (January 2018): 251525641875611. http://dx.doi.org/10.1177/2515256418756112.
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Lipid droplets (LDs) serve as specialized cytoplasmic organelles that harbor energy-rich lipids for long-term storage and may be mobilized as nutrient sources during extended starvation. How cells coordinate LD biogenesis and utilization in response to fluctuations in nutrient availability remains poorly understood. Here, we discuss our recent work revealing how yeast spatially organize LD budding at organelle contacts formed between the endoplasmic reticulum and yeast vacuole/lysosome (sites known as nucleus-vacuole junctions [NVJs]). During times of imminent nutrient exhaustion, we observe blooms of stress-induced LDs surrounding the NVJ and find that this LD clustering is regulated by NVJ-resident protein Mdm1. We also discuss several emerging studies revealing specific proteins that demarcate a subpopulation of NVJ-associated LDs. Collectively, these studies reveal a previously unappreciated role for the spatial compartmentalization of LDs at organelle contacts and highlight an important role for interorganellar cross talk in LD dynamics under times of nutritional stress.
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Charrasse, Sophie, Franck Comunale, Sylvain De Rossi, Arnaud Echard, and Cécile Gauthier-Rouvière. "Rab35 regulates cadherin-mediated adherens junction formation and myoblast fusion." Molecular Biology of the Cell 24, no. 3 (February 2013): 234–45. http://dx.doi.org/10.1091/mbc.e12-02-0167.
Full textAbstract:
Cadherins are homophilic cell–cell adhesion molecules implicated in many fundamental processes, such as morphogenesis, cell growth, and differentiation. They accumulate at cell–cell contact sites and assemble into large macromolecular complexes named adherens junctions (AJs). Cadherin targeting and function are regulated by various cellular processes, many players of which remain to be uncovered. Here we identify the small GTPase Rab35 as a new regulator of cadherin trafficking and stabilization at cell–cell contacts in C2C12 myoblasts and HeLa cells. We find that Rab35 accumulates at cell–cell contacts in a cadherin-dependent manner. Knockdown of Rab35 or expression of a dominant-negative form of Rab35 impaired N- and M-cadherin recruitment to cell–cell contacts, their stabilization at the plasma membrane, and association with p120 catenin and led to their accumulation in transferrin-, clathrin-, and AP-2–positive intracellular vesicles. We also find that Rab35 function is required for PIP5KIγ accumulation at cell–cell contacts and phosphatidyl inositol 4,5-bisphosphate production, which is involved in cadherin stabilization at contact sites. Finally, we show that Rab35 regulates myoblast fusion, a major cellular process under the control of cadherin-dependent signaling. Taken together, these results reveal that Rab35 regulates cadherin-dependent AJ formation and myoblast fusion.
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Peng, Wesley, Yvette C. Wong, and Dimitri Krainc. "Mitochondria-lysosome contacts regulate mitochondrial Ca2+dynamics via lysosomal TRPML1." Proceedings of the National Academy of Sciences 117, no. 32 (July 23, 2020): 19266–75. http://dx.doi.org/10.1073/pnas.2003236117.
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Mitochondria and lysosomes are critical for cellular homeostasis, and dysfunction of both organelles has been implicated in numerous diseases. Recently, interorganelle contacts between mitochondria and lysosomes were identified and found to regulate mitochondrial dynamics. However, whether mitochondria–lysosome contacts serve additional functions by facilitating the direct transfer of metabolites or ions between the two organelles has not been elucidated. Here, using high spatial and temporal resolution live-cell microscopy, we identified a role for mitochondria–lysosome contacts in regulating mitochondrial calcium dynamics through the lysosomal calcium efflux channel, transient receptor potential mucolipin 1 (TRPML1). Lysosomal calcium release by TRPML1 promotes calcium transfer to mitochondria, which was mediated by tethering of mitochondria–lysosome contact sites. Moreover, mitochondrial calcium uptake at mitochondria–lysosome contact sites was modulated by the outer and inner mitochondrial membrane channels, voltage-dependent anion channel 1 and the mitochondrial calcium uniporter, respectively. Since loss of TRPML1 function results in the lysosomal storage disorder mucolipidosis type IV (MLIV), we examined MLIV patient fibroblasts and found both altered mitochondria–lysosome contact dynamics and defective contact-dependent mitochondrial calcium uptake. Thus, our work highlights mitochondria–lysosome contacts as key contributors to interorganelle calcium dynamics and their potential role in the pathophysiology of disorders characterized by dysfunctional mitochondria or lysosomes.
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Conforti, G., C. Dominguez-Jimenez, E. Ronne, G. Hoyer-Hansen, and E. Dejana. "Cell-surface plasminogen activation causes a retraction of in vitro cultured human umbilical vein endothelial cell monolayer." Blood 83, no. 4 (February 15, 1994): 994–1005. http://dx.doi.org/10.1182/blood.v83.4.994.994.
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Abstract Vascular endothelium forms a dynamic interface between blood and underlying tissues. Endothelial monolayer integrity is required for controlled vascular permeability and to preclude exposure of subendothelial cell matrix to circulating cells. Recent studies have established that cultured human umbilical vein endothelial cells (ECs) express receptors for plasminogen (plg) and urokinase-like plasminogen activator (uPA). In the present study, we provide evidence that in EC, uPA receptor is present in focal contacts and at cell-cell contact sites. In these cells, addition of plg and uPA to confluent EC generates a retraction of the monolayer that is evidenced by loss of cell-cell contacts and increase in monolayer permeability. The phenomenon is reversible even after 6 hours of plg-uPA treatment. Inhibition of plg-uPA effect is obtained with plasmin inhibitors, as well as reagents that block binding of uPA or plg to the cell surface. The retractive effect of plg-uPA is concomitant to surface activation of plasminogen and to the loss of cell-cell activation of plg can induce EC retraction, possibly by causing proteolysis at specific cell-cell contacts and cell-matrix sites. This process may be important in mediating the passage of metastatic tumor cells through an intact EC monolayer as well as in regulating contacts between circulating cells and endothelium.
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Conforti, G., C. Dominguez-Jimenez, E. Ronne, G. Hoyer-Hansen, and E. Dejana. "Cell-surface plasminogen activation causes a retraction of in vitro cultured human umbilical vein endothelial cell monolayer." Blood 83, no. 4 (February 15, 1994): 994–1005. http://dx.doi.org/10.1182/blood.v83.4.994.bloodjournal834994.
Full textAbstract:
Vascular endothelium forms a dynamic interface between blood and underlying tissues. Endothelial monolayer integrity is required for controlled vascular permeability and to preclude exposure of subendothelial cell matrix to circulating cells. Recent studies have established that cultured human umbilical vein endothelial cells (ECs) express receptors for plasminogen (plg) and urokinase-like plasminogen activator (uPA). In the present study, we provide evidence that in EC, uPA receptor is present in focal contacts and at cell-cell contact sites. In these cells, addition of plg and uPA to confluent EC generates a retraction of the monolayer that is evidenced by loss of cell-cell contacts and increase in monolayer permeability. The phenomenon is reversible even after 6 hours of plg-uPA treatment. Inhibition of plg-uPA effect is obtained with plasmin inhibitors, as well as reagents that block binding of uPA or plg to the cell surface. The retractive effect of plg-uPA is concomitant to surface activation of plasminogen and to the loss of cell-cell activation of plg can induce EC retraction, possibly by causing proteolysis at specific cell-cell contacts and cell-matrix sites. This process may be important in mediating the passage of metastatic tumor cells through an intact EC monolayer as well as in regulating contacts between circulating cells and endothelium.
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Joshi, Amit S., Joey V. Ragusa, William A. Prinz, and Sarah Cohen. "Multiple C2 domain–containing transmembrane proteins promote lipid droplet biogenesis and growth at specialized endoplasmic reticulum subdomains." Molecular Biology of the Cell 32, no. 12 (June 1, 2021): 1147–57. http://dx.doi.org/10.1091/mbc.e20-09-0590.
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MCTPs can tubulate the ER via reticulon homology domains. They localize to ER subdomains that are sites of lipid droplet (LD) biogenesis. MCTP reticulon homology domains promote LD biogenesis, while C2 domains mediate ER-LD contacts to promote LD growth. MCTPs may function more broadly to link ER tubules with organelle contact sites.
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Gilmore, AP, C. Wood, V. Ohanian, P. Jackson, B. Patel, DJ Rees, RO Hynes, and DR Critchley. "The cytoskeletal protein talin contains at least two distinct vinculin binding domains." Journal of Cell Biology 122, no. 2 (July 15, 1993): 337–47. http://dx.doi.org/10.1083/jcb.122.2.337.
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We have mapped the vinculin-binding sites in the cytoskeletal protein talin as well as those sequences which target the talin molecule to focal contacts. Using a series of overlapping talin-fusion proteins expressed in E. coli and 125I-vinculin in both gel-overlay and microtitre well binding assays, we present evidence for three separable binding sites for vinculin. All three are in the tail segment of talin (residues 434-2541) and are recognized by the same fragment of vinculin (residues 1-258). Two sites are adjacent to each other and span residues 498-950, and the third site is more than 700 residues distant in the primary sequence. Scatchard analysis of 125I-vinculin binding to talin also indicates three sites, each with a similar affinity (Kd = 2-6 x 10(-7) M). We also detect a substoichiometric interaction of higher affinity (Kd = 3 x 10(-8) M) which remains unexplained. By expressing regions of the chicken talin molecule in heterologous cells, we have shown that the sequences required to target talin to focal contacts overlap those which bind vinculin.
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Barazzuol, Lucia, Flavia Giamogante, Marisa Brini, and Tito Calì. "PINK1/Parkin Mediated Mitophagy, Ca2+ Signalling, and ER–Mitochondria Contacts in Parkinson’s Disease." International Journal of Molecular Sciences 21, no. 5 (March 5, 2020): 1772. http://dx.doi.org/10.3390/ijms21051772.
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Endoplasmic reticulum (ER)–mitochondria contact sites are critical structures for cellular function. They are implicated in a plethora of cellular processes, including Ca2+ signalling and mitophagy, the selective degradation of damaged mitochondria. Phosphatase and tensin homolog (PTEN)-induced kinase (PINK) and Parkin proteins, whose mutations are associated with familial forms of Parkinson’s disease, are two of the best characterized mitophagy players. They accumulate at ER–mitochondria contact sites and modulate organelles crosstalk. Alterations in ER–mitochondria tethering are a common hallmark of many neurodegenerative diseases including Parkinson’s disease. Here, we summarize the current knowledge on the involvement of PINK1 and Parkin at the ER–mitochondria contact sites and their role in the modulation of Ca2+ signalling and mitophagy.
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Peruzzo, Roberta, Roberto Costa, Magdalena Bachmann, Luigi Leanza, and Ildikò Szabò. "Mitochondrial Metabolism, Contact Sites and Cellular Calcium Signaling: Implications for Tumorigenesis." Cancers 12, no. 9 (September 10, 2020): 2574. http://dx.doi.org/10.3390/cancers12092574.
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Mitochondria are organelles that are mainly involved in the generation of ATP by cellular respiration. In addition, they modulate several intracellular functions, ranging from cell proliferation and differentiation to cell death. Importantly, mitochondria are social and can interact with other organelles, such as the Endoplasmic Reticulum, lysosomes and peroxisomes. This symbiotic relationship gives advantages to both partners in regulating some of their functions related to several aspects of cell survival, metabolism, sensitivity to cell death and metastasis, which can all finally contribute to tumorigenesis. Moreover, growing evidence indicates that modulation of the length and/or numbers of these contacts, as well as of the distance between the two engaged organelles, impacts both on their function as well as on cellular signaling. In this review, we discuss recent advances in the field of contacts and communication between mitochondria and other intracellular organelles, focusing on how the tuning of mitochondrial function might impact on both the interaction with other organelles as well as on intracellular signaling in cancer development and progression, with a special focus on calcium signaling.
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Baciu, P. C., and P. F. Goetinck. "Protein kinase C regulates the recruitment of syndecan-4 into focal contacts." Molecular Biology of the Cell 6, no. 11 (November 1995): 1503–13. http://dx.doi.org/10.1091/mbc.6.11.1503.
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Cell surface heparan sulfate proteoglycans have been implicated as co-receptors facilitating cell adhesion and growth factor binding. Recent studies on the role of a family of transmembrane heparan sulfate proteoglycans, syndecans, in cell adhesion has identified one member, syndecan-4, to be present within focal contacts. The current study investigates the mechanisms regulating the association of syndecan-4 with focal contacts based upon its immunolocalization with vinculin in quiescent, serum-stimulated, and 12-0-tetradecanoylphorbol 13-acetate (TPA)-induced cultures. In quiescent cells, syndecan-4 did not localize to focal contacts. However, activation of protein kinase C by TPA or serum induces the active recruitment of syndecan-4 into focal contacts. This induction preferentially localizes syndecan-4 to focal contacts behind the leading lamella, the subnuclear region, and along the trailing edge of migratory cells. Focal contacts in either freshly adhered cells or in the leading lamellae of migrating cells did not stain for syndecan-4. In addition to the observed subcellular distribution and recruitment, syndecan-4 was observed to co-localize with endogenously synthesized fibronectin fibrils within focal contacts as well as with fibrils present in the matrix. These findings suggest that protein kinase C activation results in syndecan-4 recruitment to focal contacts and its association with sites of matrix deposition.
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Bhende, Prasanna M., and Susan M. Egan. "Amino Acid-DNA Contacts by RhaS: an AraC Family Transcription Activator." Journal of Bacteriology 181, no. 17 (September 1, 1999): 5185–92. http://dx.doi.org/10.1128/jb.181.17.5185-5192.1999.
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ABSTRACT RhaS, an AraC family protein, activates rhaBADtranscription by binding to rhaI, a site consisting of two 17-bp inverted repeat half-sites. In this work, amino acids in RhaS that make base-specific contacts with rhaI were identified. Sequence similarity with AraC suggested that the first contacting motif of RhaS was a helix-turn-helix. Assays of rhaB-lacZactivation by alanine mutants within this potential motif indicated that residues 201, 202, 205, and 206 might contact rhaI. The second motif was identified based on the hypothesis that a region of especially high amino acid similarity between RhaS and RhaR (another AraC family member) might contact the nearly identical DNA sequences in one major groove of their half-sites. We first made targeted, random mutations and then made alanine substitutions within this region of RhaS. Our analysis identified residues 247, 248, 250, 252, 253, and 254 as potentially important for DNA binding. A genetic loss-of-contact approach was used to identify whether any of the RhaS amino acids in the first or second contacting motif make base-specific DNA contacts. In motif 1, we found that Arg202 and Arg206 both make specific contacts with bp −65 and −67 in rhaI 1, and that Arg202 contacts −46 and Arg206 contacts −48 inrhaI 2. In motif 2, we found that Asp250 and Asn252 both contact the bp −79 in rhaI 1. Alignment with the recently crystallized MarA protein suggest that both RhaS motifs are likely helix-turn-helix DNA-binding motifs.
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Salmon, C., Y. Miyashita, J. Marchelidon, and Y. A. Fontaine. "Mise en évidence et propriétés des sites de liaison spécifique pour la gonadotropine de carpe dans des préparations membranaires d'ovaire d'Anguille (Anguilla anguilla L.)." General and Comparative Endocrinology 65, no. 2 (February 1987): 203–11. http://dx.doi.org/10.1016/0016-6480(87)90167-5.
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Yamamoto, Takaharu, Naozumi Harada, Kyoko Kano, Shin-ichiro Taya, Eli Canaani, Yoshiharu Matsuura, Akira Mizoguchi, Chizuka Ide, and Kozo Kaibuchi. "The Ras Target AF-6 Interacts with ZO-1 and Serves as a Peripheral Component of Tight Junctions in Epithelial Cells." Journal of Cell Biology 139, no. 3 (November 3, 1997): 785–95. http://dx.doi.org/10.1083/jcb.139.3.785.
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The dynamic rearrangement of cell–cell junctions such as tight junctions and adherens junctions is a critical step in various cellular processes, including establishment of epithelial cell polarity and developmental patterning. Tight junctions are mediated by molecules such as occludin and its associated ZO-1 and ZO-2, and adherens junctions are mediated by adhesion molecules such as cadherin and its associated catenins. The transformation of epithelial cells by activated Ras results in the perturbation of cell–cell contacts. We previously identified the ALL-1 fusion partner from chromosome 6 (AF-6) as a Ras target. AF-6 has the PDZ domain, which is thought to localize AF-6 at the specialized sites of plasma membranes such as cell–cell contact sites. We investigated roles of Ras and AF-6 in the regulation of cell–cell contacts and found that AF-6 accumulated at the cell–cell contact sites of polarized MDCKII epithelial cells and had a distribution similar to that of ZO-1 but somewhat different from those of catenins. Immunoelectron microscopy revealed a close association between AF-6 and ZO-1 at the tight junctions of MDCKII cells. Native and recombinant AF-6 interacted with ZO-1 in vitro. ZO-1 interacted with the Ras-binding domain of AF-6, and this interaction was inhibited by activated Ras. AF-6 accumulated with ZO-1 at the cell–cell contact sites in cells lacking tight junctions such as Rat1 fibroblasts and PC12 rat pheochromocytoma cells. The overexpression of activated Ras in Rat1 cells resulted in the perturbation of cell–cell contacts, followed by a decrease of the accumulation of AF-6 and ZO-1 at the cell surface. These results indicate that AF-6 serves as one of the peripheral components of tight junctions in epithelial cells and cell–cell adhesions in nonepithelial cells, and that AF-6 may participate in the regulation of cell–cell contacts, including tight junctions, via direct interaction with ZO-1 downstream of Ras.
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Sytnyk, Vladimir, Iryna Leshchyns'ka, Markus Delling, Galina Dityateva, Alexander Dityatev, and Melitta Schachner. "Neural cell adhesion molecule promotes accumulation of TGN organelles at sites of neuron-to-neuron contacts." Journal of Cell Biology 159, no. 4 (November 18, 2002): 649–61. http://dx.doi.org/10.1083/jcb.200205098.
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Transformation of a contact between axon and dendrite into a synapse is accompanied by accumulation of the synaptic machinery at this site, being delivered in intracellular organelles mainly of TGN origin. Here, we report that in cultured hippocampal neurons, TGN organelles are linked via spectrin to clusters of the neural cell adhesion molecule (NCAM) in the plasma membrane. These complexes are translocated along neurites and trapped at sites of initial neurite-to-neurite contacts within several minutes after initial contact formation. The accumulation of TGN organelles at contacts with NCAM-deficient neurons is reduced when compared with wild-type cells, suggesting that NCAM mediates the anchoring of intracellular organelles in nascent synapses.
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Hertlein, Vanessa, Hector Flores-Romero, Kushal K. Das, Sebastian Fischer, Michael Heunemann, Maria Calleja-Felipe, Shira Knafo, et al. "MERLIN: a novel BRET-based proximity biosensor for studying mitochondria–ER contact sites." Life Science Alliance 3, no. 1 (December 9, 2019): e201900600. http://dx.doi.org/10.26508/lsa.201900600.
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The contacts between the ER and mitochondria play a key role in cellular functions such as the exchange of lipids and calcium between both organelles, as well as in apoptosis and autophagy signaling. The molecular architecture and spatiotemporal regulation of these distinct contact regions remain obscure and there is a need for new tools that enable tackling these questions. Here, we present a new bioluminescence resonance energy transfer–based biosensor for the quantitative analysis of distances between the ER and mitochondria that we call MERLIN (Mitochondria–ER Length Indicator Nanosensor). The main advantages of MERLIN compared with available alternatives are that it does not rely on the formation of artificial physical links between the two organelles, which could lead to artifacts, and that it allows to study contact site reversibility and dynamics. We show the applicability of MERLIN by characterizing the role of the mitochondrial dynamics machinery on the contacts of this organelle with the ER.
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Cao, Chen, Lincong Wang, Xiaoyang Chen, Shuxue Zou, Guishen Wang, and Shutan Xu. "Amino Acids in Nine Ligand-Prefer Ramachandran Regions." BioMed Research International 2015 (2015): 1–10. http://dx.doi.org/10.1155/2015/757495.
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Several secondary structures, such asπ-helix and left-handed helix, have been frequently identified at protein ligand-binding sites. A secondary structure is considered to be constrained to a specific region of dihedral angles. However, a comprehensive analysis of the correlation between main chain dihedral angles and ligand-binding sites has not been performed. We undertook an extensive analysis of the relationship between dihedral angles in proteins and their distance to ligand-binding sites, frequency of occurrence, molecular potential energy, amino acid composition, van der Waals contacts, and hydrogen bonds with ligands. The results showed that the values of dihedral angles have a strong preference for ligand-binding sites at certain regions in the Ramachandran plot. We discovered that amino acids preceding the ligand-preferϕ/ψbox residues are exposed more to solvents, whereas amino acids following ligand-preferϕ/ψbox residues form more hydrogen bonds and van der Waals contacts with ligands. Our method exhibited a similar performance compared with the program Ligsite-csc for both ligand-bound structures and ligand-free structures when just one ligand-binding site was predicted. These results should be useful for the prediction of protein ligand-binding sites and for analysing the relationship between structure and function.
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Simon, Ágnes, Csaba Magyar, László Héja, and Julianna Kardos. "Peptide Binding Sites of Connexin Proteins." Chemistry 2, no. 3 (July 14, 2020): 662–73. http://dx.doi.org/10.3390/chemistry2030042.
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Intercellular gap junction (GJ) contacts formed by the coupling of connexin (Cx) hemichannels (HCs) embedded into the plasma membranes of neighboring cells play significant role in the development, signaling and malfunctions of mammalian tissues. Understanding and targeting GJ functions, however, calls for finding valid Cx subtype-specific inhibitors. We conjecture the lack of information about binding interactions between the GJ interface forming extracellular EL1 and EL2 loops and peptide mimetics designed to specifically inhibit Cx43HC coupling to Cx43GJ. Here, we explore active spots at the GJ interface using known peptide inhibitors that mimic various segments of EL1 and EL2. Binding interactions of these peptide inhibitors and the non-peptide inhibitor quinine has been modelled in combination with the use of blind docking molecular mechanics (MM). The neuron-specific Cx36HC and astrocyte-specific Cx43HC subtypes were modelled with a template derived from the high-resolution structure of Cx26GJ. GJ-coupled and free Cx36HC and Cx43HC models were obtained by dissection of GJs (GJ-coupled) followed by 50 ns molecular dynamics (free). Molecular mechanics (MM) calculations were performed by the docking of inhibitors, explicitly the designed Cx43 EL1 or EL2 loop sequence mimetics (GAP26, P5 or P180–195, GAP27, Peptide5, respectively) and the Cx36 subtype-specific quinine into the model structures. In order to explore specific binding interactions between inhibitors and CxHC subtypes, MM/Generalized Born Surface Area (MM/GBSA) ΔGbind values for representative conformers of peptide mimetics and quinine were evaluated by mapping the binding surface of Cx36HC and Cx43HC for all inhibitors. Quinine specifically contacts Cx36 EL1 residues V54-C55-N56-T57-L58, P60 and N63. Blocking the vestibule by the side of Cx36HC entry, quinine explicitly interacts with the non-conserved V54, L58, N63 residues of Cx36 EL1. In addition, our work challenges the predicted specificity of peptide mimetics, showing that the docking site of peptides is unrelated to the location of the sequence they mimic. Binding features, such as unaffected EL2 residues and the lack of Cx43 subtype-specificity of peptide mimetics, suggest critical roles for peptide stringency and dimension, possibly pertaining to the Cx subtype-specificity of peptide inhibitors.
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Antonov, Ivan, and Yulia A. Medvedeva. "Triplex target sites of MEG3 RNA-chromatin interactions." F1000Research 7 (January 17, 2018): 76. http://dx.doi.org/10.12688/f1000research.13522.1.
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Many long noncoding RNAs are bound to chromatin. MEG3 binds to multiple different genomic locations, containing GA-rich motifs, and form RNA-DNA triplex structures. In this work, we test whether the MEG3 binding sites are specific enough to be regulated by a particular lncRNA. We show that at least in the case of MEG3, a subset of the triplex target sites (TTS) is able to hybridize with various different RNAs almost irrespectively of their sequences. Nowadays, the role of chromatin bound RNAs in the formation of 3D chromatin structure is actively discussed. We speculate that such universal TTSs may contribute to establishing long-distance chromosomal contacts.
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Myöhänen, H. T., R. W. Stephens, K. Hedman, H. Tapiovaara, E. Rønne, G. Høyer-Hansen, K. Danø, and A. Vaheri. "Distribution and lateral mobility of the urokinase-receptor complex at the cell surface." Journal of Histochemistry & Cytochemistry 41, no. 9 (September 1993): 1291–301. http://dx.doi.org/10.1177/41.9.8394852.
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Pro-urokinase (pro-uPA) and activated uPA are confined to focal adhesions and cell-cell contacts. We studied the distribution of the uPA receptor (uPAR) on human fibroblasts (HES) and rhabdomyosarcoma (RD) cells by immunofluorescence and immunoelectron microscopy. Two monoclonal antibodies (MAb) utilized were against uPAR: MAb R4, which reacts with occupied and unoccupied uPAR, was concentrated at focal adhesions; MAb R3 reacting with unoccupied receptor stained cell surfaces diffusely. MAb R4 stained cell-cell contacts, tips of microspikes, and co-localized with vinculin. Of the matrix and integrin components tested, alpha v beta 3 integrin was found at focal adhesions but more centrally than uPAR. Since uPAR is anchored to the plasma membrane through a GPI lipid, we studied its mobility by antibody-induced clustering. This revealed that unoccupied uPAR was relatively mobile; MAb R3 redistributed it to clusters. In contrast, uPAR R4 and uPA antibodies at the focal contact sites remained mostly within focal contacts. Addition of exogenous uPA resulted in loss of R3 staining and increase of uPA in focal adhesions. These results suggest that occupancy of the receptor with uPA is associated with localization to cell contact sites and restricted lateral mobility.
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Kaverina, Irina, Olga Krylyshkina, and J. Victor Small. "Microtubule Targeting of Substrate Contacts Promotes Their Relaxation and Dissociation." Journal of Cell Biology 146, no. 5 (September 6, 1999): 1033–44. http://dx.doi.org/10.1083/jcb.146.5.1033.
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We recently showed that substrate contact sites in living fibroblasts are specifically targeted by microtubules (Kaverina, I., K. Rottner, and J.V. Small. 1998. J. Cell Biol. 142:181–190). Evidence is now provided that microtubule contact targeting plays a role in the modulation of substrate contact dynamics. The results are derived from spreading and polarized goldfish fibroblasts in which microtubules and contact sites were simultaneously visualized using proteins conjugated with Cy-3, rhodamine, or green fluorescent protein. For cells allowed to spread in the presence of nocodazole the turnover of contacts was retarded, as compared with controls and adhesions that were retained under the cell body were dissociated after microtubule reassembly. In polarized cells, small focal complexes were found at the protruding cell front and larger adhesions, corresponding to focal adhesions, at the retracting flanks and rear. At retracting edges, multiple microtubule contact targeting preceded contact release and cell edge retraction. The same effect could be observed in spread cells, in which microtubules were allowed to reassemble after local disassembly by the application of nocodazole to one cell edge. At the protruding front of polarized cells, focal complexes were also targeted and as a result remained either unchanged in size or, more rarely, were disassembled. Conversely, when contact targeting at the cell front was prevented by freezing microtubule growth with 20 nM taxol and protrusion stimulated by the injection of constitutively active Rac, peripheral focal complexes became abnormally enlarged. We further found that the local application of inhibitors of myosin contractility to cell edges bearing focal adhesions induced the same contact dissociation and edge retraction as observed after microtubule targeting. Our data are consistent with a mechanism whereby microtubules deliver localized doses of relaxing signals to contact sites to retard or reverse their development. We propose that it is via this route that microtubules exert their well-established control on cell polarity.
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Sun, Elizabeth Wen, Andrés Guillén-Samander, Xin Bian, Yumei Wu, Yiying Cai, Mirko Messa, and Pietro De Camilli. "Lipid transporter TMEM24/C2CD2L is a Ca2+-regulated component of ER–plasma membrane contacts in mammalian neurons." Proceedings of the National Academy of Sciences 116, no. 12 (February 28, 2019): 5775–84. http://dx.doi.org/10.1073/pnas.1820156116.
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Close appositions between the endoplasmic reticulum (ER) and the plasma membrane (PM) are a general feature of all cells and are abundant in neurons. A function of these appositions is lipid transport between the two adjacent bilayers via tethering proteins that also contain lipid transport modules. However, little is known about the properties and dynamics of these proteins in neurons. Here we focused on TMEM24/C2CD2L, an ER-localized SMP domain containing phospholipid transporter expressed at high levels in the brain, previously shown to be a component of ER–PM contacts in pancreatic β-cells. TMEM24 is enriched in neurons versus glial cells and its levels increase in parallel with neuronal differentiation. It populates ER–PM contacts in resting neurons, but elevations of cytosolic Ca2+mediated by experimental manipulations or spontaneous activity induce its transient redistribution throughout the entire ER. Dissociation of TMEM24 from the plasma membrane is mediated by phosphorylation of an array of sites in the C-terminal region of the protein. These sites are only partially conserved in C2CD2, the paralogue of TMEM24 primarily expressed in nonneuronal tissues, which correspondingly display a much lower sensitivity to Ca2+elevations. ER–PM contacts in neurons are also sites where Kv2 (the major delayed rectifier K+channels in brain) and other PM and ER ion channels are concentrated, raising the possibility of a regulatory feedback mechanism between neuronal excitability and lipid exchange between the ER and the PM.
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Sassano, Maria Livia, and Patrizia Agostinis. "Staying in touch: Taking a closer look at ER–Golgi contact sites." Journal of Cell Biology 218, no. 3 (February 7, 2019): 729–31. http://dx.doi.org/10.1083/jcb.201901039.
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ER–Golgi contact sites regulate lipid homeostasis and trafficking across the trans-Golgi network. However, their molecular nature is elusive. In this issue, Venditti et al. (2019. J. Cell Biol. https://doi.org/10.1083/jcb.201812020 and https://doi.org/10.1083/jcb.201812021) shine new light on the molecular determinants coupling lipid exchange and cargo exit with maintenance of ER–Golgi contacts.
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Reichler, Mary R., Awal Khan, Timothy R. Sterling, Hui Zhao, Bin Chen, Yan Yuan, Joyce Moran, et al. "Risk Factors for Tuberculosis and Effect of Preventive Therapy Among Close Contacts of Persons With Infectious Tuberculosis." Clinical Infectious Diseases 70, no. 8 (May 24, 2019): 1562–72. http://dx.doi.org/10.1093/cid/ciz438.
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Abstract Background Close contacts of persons with pulmonary tuberculosis (TB) have high rates of TB disease. Methods We prospectively enrolled TB patients and their close contacts at 9 US/Canadian sites. TB patients and contacts were interviewed to identify index patient, contact, and exposure risk factors for TB. Contacts were evaluated for latent TB infection (LTBI) and TB, and the effectiveness of LTBI treatment for preventing contact TB was examined. Results Among 4490 close contacts, multivariable risk factors for TB were age ≤5 years, US/Canadian birth, human immunodeficiency virus infection, skin test induration ≥10 mm, shared bedroom with an index patient, exposure to more than 1 index patient, and index patient weight loss (P < .05 for each). Of 1406 skin test–positive contacts, TB developed in 49 (9.8%) of 446 who did not initiate treatment, 8 (1.8%) of 443 who received partial treatment, and 1 (0.2%) of 517 who completed treatment (1951, 290, and 31 cases/100 000 person-years, respectively; P < .001). TB was diagnosed in 4.2% of US/Canadian-born compared with 2.3% of foreign-born contacts (P = .002), and TB rates for US/Canadian-born and foreign-born contacts who did not initiate treatment were 3592 and 811 per 100 000 person-years, respectively (P < .001). Conclusions Treatment for LTBI was highly effective in preventing TB among close contacts of infectious TB patients. Several index patient, contact, and exposure characteristics associated with increased risk of contact TB were identified. These findings help inform contact investigation, LTBI treatment, and other public health prevention efforts.
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Bascom, Gavin D., Christopher G. Myers, and Tamar Schlick. "Mesoscale modeling reveals formation of an epigenetically driven HOXC gene hub." Proceedings of the National Academy of Sciences 116, no. 11 (February 4, 2019): 4955–62. http://dx.doi.org/10.1073/pnas.1816424116.
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Gene expression is orchestrated at the structural level by nucleosome positioning, histone tail acetylation, and linker histone (LH) binding. Here, we integrate available data on nucleosome positioning, nucleosome-free regions (NFRs), acetylation islands, and LH binding sites to “fold” in silico the 55-kb HOXC gene cluster and investigate the role of each feature on the gene’s folding. The gene cluster spontaneously forms a dynamic connection hub, characterized by hierarchical loops which accommodate multiple contacts simultaneously and decrease the average distance between promoters by ∼100 nm. Contact probability matrices exhibit “stripes” near promoter regions, a feature associated with transcriptional regulation. Interestingly, while LH proteins alone decrease long-range contacts and acetylation alone increases transient contacts, combined LH and acetylation produce long-range contacts. Thus, our work emphasizes how chromatin architecture is coordinated strongly by epigenetic factors and opens the way for nucleosome resolution models incorporating epigenetic modifications to understand and predict gene activity.
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Krols, Michiel, Geert Bultynck, and Sophie Janssens. "ER–Mitochondria contact sites: A new regulator of cellular calcium flux comes into play." Journal of Cell Biology 214, no. 4 (August 15, 2016): 367–70. http://dx.doi.org/10.1083/jcb.201607124.
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Endoplasmic reticulum (ER)–mitochondria membrane contacts are hotspots for calcium signaling. In this issue, Raturi et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201512077) show that the thioredoxin TMX1 inhibits the calcium pump SERCA2b at ER–mitochondria contact sites, thereby affecting ER–mitochondrial calcium transfer and mitochondrial bioenergetics.
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Kaverina, Irina, Klemens Rottner, and J. Victor Small. "Targeting, Capture, and Stabilization of Microtubules at Early Focal Adhesions." Journal of Cell Biology 142, no. 1 (July 13, 1998): 181–90. http://dx.doi.org/10.1083/jcb.142.1.181.
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By co-injecting fluorescent tubulin and vinculin into fish fibroblasts we have revealed a “cross talk” between microtubules and early sites of substrate contact. This mutuality was first indicated by the targeting of vinculin-rich foci by microtubules during their growth towards the cell periphery. In addition to passing directly over contact sites, the ends of single microtubules could be observed to target several contacts in succession or the same contact repetitively, with intermittent withdrawals. Targeting sometimes involved side-stepping, or the major re-routing of a microtubule, indicative of a guided, rather than a random process. The paths that microtubules followed into contacts were unrelated to the orientation of stress fiber assemblies and targeting occurred also in mouse fibroblasts that lacked a system of intermediate filaments. Further experiments with microtubule inhibitors showed that adhesion foci can: (a) capture microtubules and stabilize them against disassembly by nocodazole; and (b), act as preferred sites of microtubule polymerization, during either early recovery from nocodazole, or brief treatment with taxol. From these and other findings we speculate that microtubules are guided into substrate contact sites and through the motor-dependent delivery of signaling molecules serve to modulate their development. It is further proposed this modulation provides the route whereby microtubules exert their influence on cell shape and polarity.
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Hortsch, Michael, Diahann Homer, Jyoti Dhar Malhotra, Sherry Chang, Jason Frankel, Gregory Jefford, and Ronald R. Dubreuil. "Structural Requirements for Outside-In and Inside-Out Signaling by Drosophila Neuroglian, a Member of the L1 Family of Cell Adhesion Molecules." Journal of Cell Biology 142, no. 1 (July 13, 1998): 251–61. http://dx.doi.org/10.1083/jcb.142.1.251.
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Expression of the Drosophila cell adhesion molecule neuroglian in S2 cells leads to cell aggregation and the intracellular recruitment of ankyrin to cell contact sites. We localized the region of neuroglian that interacts with ankyrin and investigated the mechanism that limits this interaction to cell contact sites. Yeast two-hybrid analysis and expression of neuroglian deletion constructs in S2 cells identified a conserved 36-amino acid sequence that is required for ankyrin binding. Mutation of a conserved tyrosine residue within this region reduced ankyrin binding and extracellular adhesion. However, residual recruitment of ankyrin by this mutant neuroglian molecule was still limited to cell contacts, indicating that the lack of ankyrin binding at noncontact sites is not caused by tyrosine phosphorylation. A chimeric molecule, in which the extracellular domain of neuroglian was replaced with the corresponding domain from the adhesion molecule fasciclin II, also selectively recruited ankyrin to cell contacts. Thus, outside-in signaling by neuroglian in S2 cells depends on extracellular adhesion, but does not depend on any unique property of its extracellular domain. We propose that the recruitment of ankyrin to cell contact sites depends on a physical rearrangement of neuroglian in response to cell adhesion, and that ankyrin binding plays a reciprocal role in stabilizing the adhesive interaction.