Journal articles on the topic 'Receptor assembly'
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1
Ahring, Philip Kiær, Vivian Wan Yu Liao, and Thomas Balle. "Concatenated nicotinic acetylcholine receptors: A gift or a curse?" Journal of General Physiology 150, no. 3 (January 30, 2018): 453–73. http://dx.doi.org/10.1085/jgp.201711846.
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Nicotinic acetylcholine receptors (nAChRs) belong to the Cys-loop receptor family and are vital for normal mammalian brain function. Cys-loop receptors are pentameric ligand-gated ion channels formed from five identical or homologous subunits oriented around a central ion-conducting pore, which result in homomeric or heteromeric receptors, respectively. Within a given Cys-loop receptor family, many different heteromeric receptors can assemble from a common set of subunits, and understanding the properties of these heteromeric receptors is crucial for the continuing quest to generate novel treatments for human diseases. Yet this complexity also presents a hindrance for studying Cys-loop receptors in heterologous expression systems, where full control of the receptor stoichiometry and assembly is required. Therefore, subunit concatenation technology is commonly used to control receptor assembly. In theory, this methodology should facilitate full control of the stoichiometry. In reality, however, we find that commonly used constructs do not yield the expected receptor stoichiometries. With ternary or more complex receptors, concatenated subunits must assemble uniformly in only one orientation; otherwise, the resulting receptor pool will consist of receptors with mixed stoichiometries. We find that typically used constructs of α4β2 nAChR dimers, tetramers, and pentamers assemble readily in both the clockwise and the counterclockwise orientations. Consequently, we investigate the possibility of successfully directing the receptor assembly process using concatenation. We begin by investigating the three-dimensional structures of the α4β2 nAChR. Based on this, we hypothesize that the minimum linker length required to bridge the C terminus of one subunit to the N terminus of the next is shortest in the counterclockwise orientation. We then successfully express receptors with a uniform stoichiometry by systematically shortening linker lengths, proving the hypothesis correct. Our results will significantly aid future studies of heteromeric Cys-loop receptors and enable clarification of the current contradictions in the literature.
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Bollan, K., L. A. Robertson, H. Tang, and C. N. Connolly. "Multiple assembly signals in γ-aminobutyric acid (type A) receptor subunits combine to drive receptor construction and composition." Biochemical Society Transactions 31, no. 4 (August 1, 2003): 875–79. http://dx.doi.org/10.1042/bst0310875.
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Mammalian γ-aminobutyric acid type A (GABAA) receptors are constructed from a large repertoire of subunits (α1–α6, β1–β3, γ1–γ3, δ, ∊, θ and π) into a pentameric ion channel. GABAA receptor assembly occurs within the endoplasmic reticulum (ER) and involves interactions with chaperone molecules. Only specific subunit combinations can produce functional surface receptors (with a fixed stoichiometry); other subunit combinations are retained within the ER and degraded. Thus, receptor assembly occurs by defined pathways to limit the diversity of GABAA receptors. The key to understanding how receptor diversity is achieved and controlled is the identification of assembly signals capable of distinguishing between other subunit partners. Analysis of an assembly box in α1 (residues 57–68) has revealed an absolute requirement for this region in the assembly of αβ receptors. Furthermore, a selective requirement for a single amino acid (R66) is observed for the assembly of α1β2, but not α1β1 or α1β3, receptors. In addition, we have characterized an assembly signal in the β3 subunit that is capable of driving the assembly of β3, γ2β3 and α1β3 receptors. Interestingly, this signal does not appear to utilize the α1 assembly box, suggesting the presence of alternative assembly signals within the α1 subunit. Although this β3 signal is sufficient to permit the formation of βγ receptors it is not necessary, suggesting that alternative assembly signals also exist within the β3 subunit. These findings support the belief that GABAA receptor assembly occurs via multiple defined pathways that may be determined by subunit availability.
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Sarto-Jackson, Isabella, Roman Furtmueller, Margot Ernst, Sigismund Huck, and Werner Sieghart. "Spontaneous Cross-link of Mutated α1 Subunits during GABAA Receptor Assembly." Journal of Biological Chemistry 282, no. 7 (December 4, 2006): 4354–63. http://dx.doi.org/10.1074/jbc.m609676200.
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γ-Aminobutyric acid, type A (GABAA) receptor α1 subunits containing a cysteine mutation at a position in the channel mouth (H109C) surprisingly formed a spontaneous cross-link with each other in receptors composed of α1H109C, β3, and γ2 subunits. Cross-linking of two α1H109C subunits did not significantly change the affinity of [3H]muscimol or [3H]Ro15-1788 binding in α1H109Cβ3γ2 receptors, but GABA displayed a reduced potency for activating chloride currents. On reduction of the disulfide bond, however, GABA activation as well as diazepam modulation was similar in mutated and wild-type receptors, suggesting that these receptors exhibited the same subunit stoichiometry and arrangement. Disulfide bonds could not be reoxidized by copper phenanthroline after having been reduced in completely assembled receptors, suggesting that cross-linking can only occur at an early stage of assembly. The cross-link of α1H109C subunits and the subsequent transport of the resulting homodimers to the cell surface caused a reduction of the intracellular pool of α1H109C subunits and a reduced formation of completely assembled receptors. The formation of α1H109C homodimers as well as of correctly assembled GABAA receptors containing cross-linked α1H109C subunits could indicate that homodimerization of α1 subunits via contacts located in the channel mouth might be one starting point of GABAA receptor assembly. Alternatively the assembly mechanism might have started with the formation of heterodimers followed by a cross-link of mutated α1 subunits at the heterotrimeric stage. The formation of cross-linked α1H109C homodimers would then have occurred independently in a separate pathway.
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Knudson, C. B. "Hyaluronan receptor-directed assembly of chondrocyte pericellular matrix." Journal of Cell Biology 120, no. 3 (February 1, 1993): 825–34. http://dx.doi.org/10.1083/jcb.120.3.825.
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Initial assembly of extracellular matrix occurs within a zone immediately adjacent to the chondrocyte cell surface termed the cell-associated or pericellular matrix. Assembly within the pericellular matrix compartment requires specific cell-matrix interactions to occur, that are mediated via membrane receptors. The focus of this study is to elucidate the mechanisms of assembly and retention of the cartilage pericellular matrix proteoglycan aggregates important for matrix organization. Assembly of newly synthesized chondrocyte pericellular matrices was inhibited by the addition to hyaluronan hexasaccharides, competitive inhibitors of the binding of hyaluronan to its cell surface receptor. Fully assembled chondrocyte pericellular matrices were displaced using hyaluronan hexasaccharides as well. When exogenous hyaluronan was added to matrix-free chondrocytes in combination with aggrecan, a pericellular matrix equivalent in size to an endogenous matrix formed within 30 min of incubation. Addition of hyaluronan and aggrecan to glutaraldehyde-fixed chondrocytes resulted in matrix assembly comparable to live chondrocytes. These matrices could be inhibited from assembling by the addition of excess hyaluronan hexasaccharides or displaced once assembled by subsequent incubation with hyaluronan hexasaccharides. The results indicate that the aggrecanrich chondrocyte pericellular matrix is not only on a scaffolding of hyaluronan, but actually anchored to the cell surface via the interaction between hyaluronan and hyaluronan receptors.
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Letourneur, F., S. Hennecke, C. Démollière, and P. Cosson. "Steric masking of a dilysine endoplasmic reticulum retention motif during assembly of the human high affinity receptor for immunoglobulin E." Journal of Cell Biology 129, no. 4 (May 15, 1995): 971–78. http://dx.doi.org/10.1083/jcb.129.4.971.
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Signals that can cause retention in the ER have been found in the cytoplasmic domain of individual subunits of multimeric receptors destined to the cell surface. To study how ER retention motifs are masked during assembly of oligomeric receptors, we analyzed the assembly and intracellular transport of the human high-affinity receptor for immunoglobulin E expressed in COS cells. The cytoplasmic domain of the alpha chain contains a dilysine ER retention signal, which becomes nonfunctional after assembly with the gamma chain, allowing transport out of the ER of the fully assembled receptor. Juxtaposition of the cytoplasmic domains of the alpha and gamma subunits during assembly is responsible for this loss of ER retention. Substitution of the gamma chain cytoplasmic domain with cytoplasmic domains of irrelevant proteins resulted in efficient transport out of the ER of the alpha chain, demonstrating that nonspecific steric hindrance by the cytoplasmic domain of the gamma chain accounts for the masking of the ER retention signal present in the cytoplasmic domain of the alpha chain. Such a mechanism allows the ER retention machinery to discriminate between assembled and nonassembled receptors, and thus participates in quality control at the level of the ER.
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Blount, P., and J. P. Merlie. "Mutational analysis of muscle nicotinic acetylcholine receptor subunit assembly." Journal of Cell Biology 111, no. 6 (December 1, 1990): 2613–22. http://dx.doi.org/10.1083/jcb.111.6.2613.
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The structural elements required for normal maturation and assembly of the nicotinic acetylcholine receptor alpha subunit were investigated by expression of mutated subunits in transfected fibroblasts. Normally, the wild-type alpha subunit acquires high affinity alpha bungarotoxin binding in a time-dependent manner; however, mutation of the 128 and/or 142 cysteines to either serine or alanine, as well as deletion of the entire 14 amino acids in this region abolished all detectable high affinity binding. Nonglycosylated subunits that had a serine to glycine mutation in the consensus sequence also did not efficiently attain high affinity binding to toxin. In contrast, mutation of the proline at position 136 to glycine or alanine, or a double mutation of the cysteines at position 192 and 193 to serines had no effect on the acquisition of high affinity toxin binding. These data suggest that a disulfide bridge between cysteines 128 and 142 and oligosaccharide addition at asparagine 141 are required for the normal maturation of alpha subunit as assayed by high affinity toxin binding. The unassembled wild-type alpha subunit expressed in fibroblasts is normally degraded with a t1/2 of 2 h; upon assembly with the delta subunit, the degradation rate slows significantly (t1/2 greater than 13 h). All mutated alpha subunits retained the capacity to assemble with a delta subunit coexpressed in fibroblasts; however, mutated alpha subunits that were not glycosylated or did not acquire high affinity toxin binding were rapidly degraded (t1/2 = 20 min to 2 h) regardless of whether or not they assembled with the delta subunit. Assembly and rapid degradation of nonglycosylated acetylcholine receptor (AChR) subunits and subunit complexes were also observed in tunicamycin-treated BC3H-1 cells, a mouse musclelike cell line that normally expresses functional AChR. Hence, rapid degradation may be one form of regulation assuring that only correctly processed and assembled subunits accumulate, and ultimately make functional receptors in AChR-expressing cells.
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Millar, N. S. "Assembly and subunit diversity of nicotinic acetylcholine receptors." Biochemical Society Transactions 31, no. 4 (August 1, 2003): 869–74. http://dx.doi.org/10.1042/bst0310869.
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Nicotinic acetylcholine receptors (nAChRs) are a diverse family of neurotransmitter-gated ion channels which contain five transmembrane subunits arranged around a central pore. Distinct receptor subtypes are expressed at the vertebrate skeletal neuromuscular junction, in mechanosensory cells and within the central and peripheral nervous systems. A total of 17 nAChR subunits (α1–α10, β1–β4, γ, δ and ∊) have been identified in vertebrate species, which can co-assemble to generate a wide variety of nAChRs. Nicotinic receptors also constitute an abundant and diverse family of receptors in invertebrates. As a consequence of studies which have been conducted with both native and recombinant nAChRs, the subunit composition of nAChRs and the rules governing subunit co-assembly are becoming clearer. In this paper the extent of nAChR subunit diversity and evidence for receptor subunit composition is reviewed.
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Pratt, William B., Mario D. Galigniana, Yoshihiro Morishima, and Patrick J. M. Murphy. "Role of molecular chaperones in steroid receptor action." Essays in Biochemistry 40 (June 1, 2004): 41–58. http://dx.doi.org/10.1042/bse0400041.
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Unliganded steroid receptors are assembled into heterocomplexes with heat-shock protein (hsp) 90 by a multiprotein chaperone machinery. In addition to binding the receptors at the chaperone site, hsp90 binds cofactors at other sites that are part of the assembly machinery, as well as immunophilins that connect the assembled receptor-hsp90 heterocomplexes to a protein trafficking pathway. The hsp90-/hsp70-based chaperone machinery interacts with the unliganded glucocorticoid receptor to open the steroid-binding cleft to access by a steroid, and the machinery interacts in very dynamic fashion with the liganded, transformed receptor to facilitate its translocation along microtubular highways to the nucleus. In the nucleus, the chaperone machinery interacts with the receptor in transcriptional regulatory complexes after hormone dissociation to release the receptor and terminate transcriptional activation. By forming heterocomplexes with hsp90, the chaperone machinery stabilizes the receptor to degradation by the ubiquitin-proteasome pathway of proteolysis.
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Ball, Stephen G., Christopher Bayley, C. Adrian Shuttleworth, and Cay M. Kielty. "Neuropilin-1 regulates platelet-derived growth factor receptor signalling in mesenchymal stem cells." Biochemical Journal 427, no. 1 (March 15, 2010): 29–40. http://dx.doi.org/10.1042/bj20091512.
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Using human MSCs (mesenchymal stem cells) lacking VEGF (vascular endothelial growth factor) receptors, we show that the pro-angiogenic receptor neuropilin-1 associates with phosphorylated PDGFRs [PDGF (platelet-derived growth factor) receptors], thereby regulating cell signalling, migration, proliferation and network assembly. Neuropilin-1 co-immunoprecipitated and co-localized with phosphorylated PDGFRs in the presence of growth factors. Neuropilin-1 knockdown blocked PDGF-AA-induced PDGFRα phosphorylation and migration, reduced PDGF-BB-induced PDGFRβ activation and migration, blocked VEGF-A activation of both PDGFRs, and attenuated proliferation. Neuropilin-1 prominently co-localized with both PDGFRs within MSC networks assembled in Matrigel™ and in the chorioallantoic membrane vasculature microenvironment, and its knockdown grossly disrupted network assembly and decreased PDGFR signalling. Thus neuropilin-1 regulates MSCs by forming ligand-specific receptor complexes that direct PDGFR signalling, especially the PDGFRα homodimer. This receptor cross-talk may control the mobilization of MSCs in neovascularization and tissue remodelling.
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Minamiki, Tsukuru, Yuki Ichikawa, and Ryoji Kurita. "The Power of Assemblies at Interfaces: Nanosensor Platforms Based on Synthetic Receptor Membranes." Sensors 20, no. 8 (April 15, 2020): 2228. http://dx.doi.org/10.3390/s20082228.
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Synthetic sensing materials (artificial receptors) are some of the most attractive components of chemical/biosensors because of their long-term stability and low cost of production. However, the strategy for the practical design of these materials toward specific molecular recognition in water is not established yet. For the construction of artificial material-based chemical/biosensors, the bottom-up assembly of these materials is one of the effective methods. This is because the driving forces of molecular recognition on the receptors could be enhanced by the integration of such kinds of materials at the ‘interfaces’, such as the boundary portion between the liquid and solid phases. Additionally, the molecular assembly of such self-assembled monolayers (SAMs) can easily be installed in transducer devices. Thus, we believe that nanosensor platforms that consist of synthetic receptor membranes on the transducer surfaces can be applied to powerful tools for high-throughput analyses of the required targets. In this review, we briefly summarize a comprehensive overview that includes the preparation techniques for molecular assemblies, the characterization methods of the interfaces, and a few examples of receptor assembly-based chemical/biosensing platforms on each transduction mechanism.
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Danino, Dganit, and Jenny E. Hinshaw. "Self-Assembly of Dynamin." Microscopy and Microanalysis 7, S2 (August 2001): 1210–11. http://dx.doi.org/10.1017/s1431927600032128.
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Dynamin is a large GTPase essential for various intracellular processes such as synaptic vesicle recycling, caveolae internalization and trafficking into and out of the Golgi. It is also involved in receptor-mediated endocytosis, and is believed to assemble at the necks of clathrin-coated pits and assist in pinching vesicles from the plasma membrane upon GTP binding and hydrolysis.Purified recombinant dynamin self-assembles into rings and spirals in low salt conditions [1]. A dynamin mutant lacking the c-terminal proline rich domain (APRD) also assembles into rings and spirals, however unlike wild type dynamin APRD constricts in the presence of GTP analogous such as GMP-PCP [2] or GTPγS. to explore differences in the behavior of the wild type and mutant dynamin we dialyzed them into different salt solutions containing various types of nucleotides and studied their assembly over time using negative staining and cryo-TEM.
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Zakrevsky, Paul, Erin Calkins, Yi-Ling Kao, Gurkeerat Singh, Vasken L. Keleshian, Stephanie Baudrey, and Luc Jaeger. "In vitro selected GUAA tetraloop-binding receptors with structural plasticity and evolvability towards natural RNA structural modules." Nucleic Acids Research 49, no. 4 (February 1, 2021): 2289–305. http://dx.doi.org/10.1093/nar/gkab021.
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Abstract GNRA tetraloop-binding receptor interactions are key components in the macromolecular assembly of a variety of functional RNAs. In nature, there is an apparent bias for GAAA/11nt receptor and GYRA/helix interactions, with the former interaction being thermodynamically more stable than the latter. While past in vitro selections allowed isolation of novel GGAA and GUGA receptors, we report herein an in vitro selection that revealed several novel classes of specific GUAA receptors with binding affinities comparable to those from natural GAAA/11nt interactions. These GUAA receptors have structural homology with double-locked bulge RNA modules naturally occurring in ribosomal RNAs. They display mutational robustness that enables exploration of the sequence/phenotypic space associated to GNRA/receptor interactions through epistasis. Their thermodynamic self-assembly fitness landscape is characterized by a rugged neutral network with possible evolutionary trajectories toward natural GNRA/receptor interactions. High throughput sequencing analysis revealed synergetic mutations located away from the tertiary interactions that positively contribute to assembly fitness. Our study suggests that the repertoire of GNRA/receptor interactions is much larger than initially thought from the analysis of natural stable RNA molecules and also provides clues for their evolution towards natural GNRA/receptors.
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Esposito, Edward A., Anthony L. Shrout, and Robert M. Weis. "Template-Directed Self-Assembly Enhances RTK Catalytic Domain Function." Journal of Biomolecular Screening 13, no. 8 (July 25, 2008): 810–16. http://dx.doi.org/10.1177/1087057108322062.
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Receptor tyrosine kinases have become important therapeutic targets because of their involvement in diseases, including cancer. Kinase domains, which are soluble and easily purified, have found widespread use in enzyme inhibitor assays, but these domains do not exhibit full function because they are isolated from the membrane. To address this shortcoming, the authors developed a simple method to restore biologically relevant function by assembling kinase domains on a nanometer-scale template, which imitates the membrane surface. Autophosphorylation of template-assembled tyrosine kinase domains from the insulin, EphB2, and Tie2 receptors led to substantially larger phosphorylation levels compared with domains assayed under conventional conditions. Template-directed assembly increased the total substrate phosphorylation of the insulin and EphB2 receptor kinase domains as much as 60-fold and 15-fold, respectively. In contrast, substrate phosphorylation by template-assembled Tie2 was much lower than conventional conditions. The lower activity observed with the template is more biologically relevant because autophosphorylation of Tie2 is self-inhibitory. These results, as well as the underlying similarity between the organization of template-assembled and natural membrane signaling environments, suggest that template-directed assembly of signaling proteins will provide widespread benefit to basic and applied signal transduction research, especially drug discovery. ( Journal of Biomolecular Screening 2008:810-816)
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Schlissel, Mark S. "Regulating antigen-receptor gene assembly." Nature Reviews Immunology 3, no. 11 (November 2003): 890–99. http://dx.doi.org/10.1038/nri1225.
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Nickel, Joachim, Walter Sebald, Jay C. Groppe, and Thomas D. Mueller. "Intricacies of BMP receptor assembly." Cytokine & Growth Factor Reviews 20, no. 5-6 (October 2009): 367–77. http://dx.doi.org/10.1016/j.cytogfr.2009.10.022.
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Su, Yan-Ye, Chang-Han Chen, Chih-Yen Chien, Wei-Che Lin, Wan-Ting Huang, and Shau-Hsuan Li. "Mitochondrial assembly receptor expression is an independent prognosticator for patients with oral tongue squamous cell carcinoma." Journal of the Renin-Angiotensin-Aldosterone System 18, no. 3 (July 2017): 147032031771790. http://dx.doi.org/10.1177/1470320317717904.
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Introduction: Recent evidence suggests that the local renin-angiotensin system has been implicated in various malignancies. The mitochondrial assembly receptor is a newly identified receptor for angiotensin peptides, angiotensin-(1-7), and has an important role in the renin-angiotensin system. However, the role of the mitochondrial assembly receptor in the prognosis of cancer patients remains unclear. The aim of this study was to evaluate the significance of mitochondrial assembly receptor signaling in the prognosis of oral tongue squamous cell carcinoma. Methods: Mitochondrial assembly receptor immunohistochemistry was examined in 151 oral tongue squamous cell carcinoma patients and was correlated with treatment outcome. The functional relevance of the mitochondrial assembly receptor in oral tongue squamous cell carcinoma cell lines was evaluated by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide reduction and bromodeoxyuridine incorporation assays. Results: Mitochondrial assembly receptor overexpression was significantly correlated with early pathological T classification ( p=0.029) and the absence of extracapsular spread ( p=0.039). Univariate analyses demonstrated that mitochondrial assembly receptor overexpression was significantly associated with superior overall survival ( p=0.012). In multivariate comparison, mitochondrial assembly receptor overexpression remained independently associated with superior overall survival ( p=0.008, hazard ratio=1.862). In vitro, angiotensin-(1-7) suppressed the cell growth in oral tongue squamous cell carcinoma cells, and this response was reversed by the mitochondrial assembly receptor antagonist, A779. Conclusion: Mitochondrial assembly receptor expression is independently associated with the prognosis of oral tongue squamous cell carcinoma patients. These findings suggest that mitochondrial assembly receptor signaling may be a promising novel target for oral tongue squamous cell carcinoma.
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Damian, Marjorie, Véronique Pons, Pedro Renault, Céline M’Kadmi, Bartholomé Delort, Lucie Hartmann, Ali I. Kaya, et al. "GHSR-D2R heteromerization modulates dopamine signaling through an effect on G protein conformation." Proceedings of the National Academy of Sciences 115, no. 17 (April 9, 2018): 4501–6. http://dx.doi.org/10.1073/pnas.1712725115.
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The growth hormone secretagogue receptor (GHSR) and dopamine receptor (D2R) have been shown to oligomerize in hypothalamic neurons with a significant effect on dopamine signaling, but the molecular processes underlying this effect are still obscure. We used here the purified GHSR and D2R to establish that these two receptors assemble in a lipid environment as a tetrameric complex composed of two each of the receptors. This complex further recruits G proteins to give rise to an assembly with only two G protein trimers bound to a receptor tetramer. We further demonstrate that receptor heteromerization directly impacts on dopamine-mediated Gi protein activation by modulating the conformation of its α-subunit. Indeed, association to the purified GHSR:D2R heteromer triggers a different active conformation of Gαi that is linked to a higher rate of GTP binding and a faster dissociation from the heteromeric receptor. This is an additional mechanism to expand the repertoire of GPCR signaling modulation that could have implications for the control of dopamine signaling in normal and physiopathological conditions.
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Colognato, Holly, Donald A. Winkelmann, and Peter D. Yurchenco. "Laminin Polymerization Induces a Receptor–Cytoskeleton Network." Journal of Cell Biology 145, no. 3 (May 3, 1999): 619–31. http://dx.doi.org/10.1083/jcb.145.3.619.
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The transition of laminin from a monomeric to a polymerized state is thought to be a crucial step in the development of basement membranes and in the case of skeletal muscle, mutations in laminin can result in severe muscular dystrophies with basement membrane defects. We have evaluated laminin polymer and receptor interactions to determine the requirements for laminin assembly on a cell surface and investigated what cellular responses might be mediated by this transition. We found that on muscle cell surfaces, laminins preferentially polymerize while bound to receptors that included dystroglycan and α7β1 integrin. These receptor interactions are mediated through laminin COOH-terminal domains that are spatially and functionally distinct from NH2-terminal polymer binding sites. This receptor-facilitated self-assembly drives rearrangement of laminin into a cell-associated polygonal network, a process that also requires actin reorganization and tyrosine phosphorylation. As a result, dystroglycan and integrin redistribute into a reciprocal network as do cortical cytoskeleton components vinculin and dystrophin. Cytoskeletal and receptor reorganization is dependent on laminin polymerization and fails in response to receptor occupancy alone (nonpolymerizing laminin). Preferential polymerization of laminin on cell surfaces, and the resulting induction of cortical architecture, is a cooperative process requiring laminin– receptor ligation, receptor-facilitated self-assembly, actin reorganization, and signaling events.
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Briesewitz, R., A. Kern, and E. E. Marcantonio. "Assembly and function of integrin receptors is dependent on opposing alpha and beta cytoplasmic domains." Molecular Biology of the Cell 6, no. 8 (August 1995): 997–1010. http://dx.doi.org/10.1091/mbc.6.8.997.
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The membrane proximal regions of integrin alpha and beta subunits are highly conserved in evolution. In particular, all integrin alpha subunits share the KXGFFKR sequence at the beginning of their cytoplasmic domains. Previous work has shown that this domain is important in integrin receptor assembly. Using chimeric integrin alpha and beta subunits, we show that the native cytoplasmic domains of both subunits must be present for efficient assembly. Most strikingly, chimeric alpha 1 and beta 1 subunits with reciprocally swapped intracellular domains dimerize selectively into collagen IV receptors expressed at high levels on the surface. However, these receptors, which bind ligand efficiently, are deficient in a variety of post-ligand binding events, including cytoskeletal association and induction of tyrosine phosphorylation. Furthermore, deletion of the distal alpha cytoplasmic domain in the swapped heterodimers leads to ligand-independent focal contact localization, which also occurs in wild-type subunits when the distal cytoplasmic domain is deleted. These results show that proper integrin assembly requires opposed alpha and beta cytoplasmic domains, and this opposition prevents ligand-independent focal contact localization. Our working hypothesis is that these two domains may associate during receptor assembly and provide the mechanism for integrin receptor latency.
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Smart, Fiona M., and Ashok R. Venkitaraman. "Inhibition of Interleukin 7 Receptor Signaling by Antigen Receptor Assembly." Journal of Experimental Medicine 191, no. 4 (February 21, 2000): 737–42. http://dx.doi.org/10.1084/jem.191.4.737.
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After the productive rearrangement of immunoglobulin (Ig) heavy chain genes, precursor (pre-)B lymphocytes undergo a limited number of cell divisions in response to interleukin (IL)-7. Here, we present evidence that this phase of IL-7–dependent expansion is constrained by an inhibitory signal initiated by antigen receptor assembly. A line of pre-B cells from normal murine bone marrow that expresses a μ heavy chain with a D-proximal VH7183.2 region divides continuously in IL-7. IL-7 responsiveness ceases upon differentiation to the μ1, κ1 stage, despite continuing expression of the IL-7 receptor (IL-7R), suggesting that antigen receptor assembly inhibits IL-7 responsiveness. This is confirmed by introduction of a rearranged λ light chain gene, which inhibits proliferative signaling through the IL-7R. Inhibition is specific to the IL-7R, because it is overcome by replacement of the IL-7R cytoplasmic domain with corresponding sequences from the closely related IL-2Rβ chain. Alteration of a single tyrosine residue, Tyr410, in the IL-7R cytoplasmic domain to phenylalanine also prevents the inhibition of proliferation after antigen receptor assembly. Thus, the loss of IL-7 responsiveness after antigen receptor assembly may be mediated through the recruitment of an inhibitory molecule to this residue. Our findings identify a novel mechanism that limits cytokine-dependent proliferation during B lymphopoiesis. This mechanism may be essential for the proper regulation of peripheral B lymphocyte numbers.
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WANAMAKER, CHRISTIAN P., JOHN C. CHRISTIANSON, and WILLIAM N. GREEN. "Regulation of Nicotinic Acetylcholine Receptor Assembly." Annals of the New York Academy of Sciences 998, no. 1 (September 2003): 66–80. http://dx.doi.org/10.1196/annals.1254.009.
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Wang, Zuo-Zhong, Stephen F. Hardy, and Zach W. Hall. "Assembly of the Nicotinic Acetylcholine Receptor." Journal of Biological Chemistry 271, no. 44 (November 1, 1996): 27575–84. http://dx.doi.org/10.1074/jbc.271.44.27575.
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Murre, Cornelis. "Epigenetics of antigen-receptor gene assembly." Current Opinion in Genetics & Development 17, no. 5 (October 2007): 415–21. http://dx.doi.org/10.1016/j.gde.2007.08.006.
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Bass, Joseph, Gavin Chiu, Yair Argon, and Donald F. Steiner. "Folding of Insulin Receptor Monomers Is Facilitated by the Molecular Chaperones Calnexin and Calreticulin and Impaired by Rapid Dimerization." Journal of Cell Biology 141, no. 3 (May 4, 1998): 637–46. http://dx.doi.org/10.1083/jcb.141.3.637.
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Many complex membrane proteins undergo subunit folding and assembly in the ER before transport to the cell surface. Receptors for insulin and insulin-like growth factor I, both integral membrane proteins and members of the family of receptor tyrosine kinases (RTKs), are unusual in that they require homodimerization before export from the ER. To better understand chaperone mechanisms in endogenous membrane protein assembly in living cells, we have examined the folding, assembly, and transport of the human insulin receptor (HIR), a dimeric RTK. Using pulse-chase labeling and nonreducing SDS-PAGE analysis, we have explored the molecular basis of several sequential maturation steps during receptor biosynthesis. Under normal growth conditions, newly synthesized receptor monomers undergo disulfide bond formation while associated with the homologous chaperones calnexin (Cnx) and calreticulin (Crt). An inhibitor of glucose trimming, castanospermine (CST), abolished binding to Cnx/Crt but also unexpectedly accelerated receptor homodimerization resulting in misfolded oligomeric proreceptors whose processing was delayed and cell surface expression was also decreased by ∼30%. Prematurely-dimerized receptors were retained in the ER and more avidly associated with the heat shock protein of 70 kD homologue binding protein. In CST-treated cells, receptor misfolding followed disordered oligomerization. Together, these studies demonstrate a chaperone function for Cnx/Crt in HIR folding in vivo and also provide evidence that folding efficiency and homodimerization are counterbalanced.
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Li, Shaohua, Patricia Liquari, Karen K. McKee, David Harrison, Raj Patel, Sean Lee, and Peter D. Yurchenco. "Laminin–sulfatide binding initiates basement membrane assembly and enables receptor signaling in Schwann cells and fibroblasts." Journal of Cell Biology 169, no. 1 (April 11, 2005): 179–89. http://dx.doi.org/10.1083/jcb.200501098.
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Endoneurial laminins (Lms), β1-integrins, and dystroglycan (DG) are important for Schwann cell (SC) ensheathment and myelination of axons. We now show that SC expression of galactosyl-sulfatide, a Lm-binding glycolipid, precedes that of Lms in developing nerves. This glycolipid anchors Lm-1 and -2 to SC surfaces by binding to their LG domains and enables basement membrane (BM) assembly. Revealingly, non–BM-forming fibroblasts become competent for BM assembly when sulfatides are intercalated into their cell surfaces. Assembly is characterized by coalescence of sulfatide, DG, and c-Src into a Lm-associated complex; by DG-dependent recruitment of utrophin and Src activation; and by integrin-dependent focal adhesion kinase phosphorylation. Collectively, our findings suggest that sulfated glycolipids are key Lm anchors that determine which cell surfaces can assemble Lms to initiate BM assembly and DG- and integrin-mediated signaling.
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Call, Matthew, Kai Wucherpfennig, and James Chou. "Structural basis of DAP12-associated intramembrane immunoreceptor assembly. (138.16)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 138.16. http://dx.doi.org/10.4049/jimmunol.184.supp.138.16.
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Abstract Many of the molecular sensors that alert lymphocytes to dangerous events such as infection or transformation are modular receptors constructed from ligand-binding subunits and signaling subunits that assemble through specific contacts within the lipid bilayer to form functional complexes. Structure-function studies focusing on the extracellular and cytoplasmic domains of activating immunoreceptors like the T cell receptor (TCR)-CD3 complex have yielded a vast store of knowledge on the mechanisms governing ligand binding and the resulting intracellular biochemical cascades. However, the mechanisms physically linking these events across the membrane to initiate immune activation remain poorly defined, and structural information on the membrane-embedded portions of receptor complexes will be critical for developing more precise models. We previously published the first structure of an immunoreceptor-associated transmembrane (TM) signaling module, the TCR-associated ζζTM dimer. We now present the NMR structure of DAP12, a functional homologue of ζζ that provides the ITAM-based signaling capabilities to more than a dozen activating receptors expressed by NK cells and other hematopoietic lineages. We have also solved a structure of the trimolecular complex DAP12-TM forms with the NK cell receptor NKG2C. These structures reveal features that allow DAP12 to assemble with a multitude of different receptors with disparate TM sequences through focused polar contacts within the membrane.
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Wójciak-Stothard, Beata, Lynn Williams, and Anne J. Ridley. "Monocyte Adhesion and Spreading on Human Endothelial Cells Is Dependent on Rho-regulated Receptor Clustering." Journal of Cell Biology 145, no. 6 (June 14, 1999): 1293–307. http://dx.doi.org/10.1083/jcb.145.6.1293.
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The GTPase Rho is known to mediate the assembly of integrin-containing focal adhesions and actin stress fibers. Here, we investigate the role of Rho in regulating the distribution of the monocyte-binding receptors E-selectin, ICAM-1, and VCAM-1 in human endothelial cells. Inhibition of Rho activity with C3 transferase or N19RhoA, a dominant negative RhoA mutant, reduced the adhesion of monocytes to activated endothelial cells and inhibited their spreading. Similar effects were observed after pretreatment of endothelial cells with cytochalasin D. In contrast, dominant negative Rac and Cdc42 proteins did not affect monocyte adhesion or spreading. C3 transferase and cytochalasin D did not alter the expression levels of monocyte-binding receptors on endothelial cells, but did inhibit clustering of E-selectin, ICAM-1, and VCAM-1 on the cell surface induced by monocyte adhesion or cross-linking antibodies. Similarly, N19RhoA inhibited receptor clustering. Monocyte adhesion and receptor cross-linking induced stress fiber assembly, and inhibitors of myosin light chain kinase prevented this response but did not affect receptor clustering. Finally, receptor clusters colocalized with ezrin/moesin/ radixin proteins. These results suggest that Rho is required in endothelial cells for the assembly of stable adhesions with monocytes via the clustering of monocyte-binding receptors and their association with the actin cytoskeleton, independent of stress fiber formation.
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Pratt, William B., and David O. Toft. "Regulation of Signaling Protein Function and Trafficking by the hsp90/hsp70-Based Chaperone Machinery." Experimental Biology and Medicine 228, no. 2 (February 2003): 111–33. http://dx.doi.org/10.1177/153537020322800201.
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Nearly 100 proteins are known to be regulated by hsp90. Most of these substrates or “client proteins” are involved in signal transduction, and they are brought into complex with hsp90 by a multlprotein hsp90/hsp70-based chaperone machinery. In addition to binding substrate proteins at the chaperone site(s), hsp90 binds cofactors at other sites that are part of the heterocomplex assembly machinery as well as immunophllins that connect assembled substrate·hsp90 complexes to protein-trafficking systems. In the 5 years since we last reviewed this subject, much has been learned about hsp90 structure, nucleotide-binding, and cochaperone interactions; the most important concept is that ATP hydrolysis by an intrinsic ATPase activity results in a conformational change in hsp90 that is required to induce conformational change in a substrate protein. The conformational change induced in steroid receptors is an opening of the steroid-binding cleft so that it can be accessed by steroid. We have now developed a minimal system of five purified proteins—hsp90, hsp70, Hop, hsp40, and p23—that assembles stable receptor·hsp90 heterocomplexes. An hsp90·Hop·hsp70·hsp40 complex opens the cleft in an ATP-dependent process to produce a receptor·hsp90 heterocomplex with hsp90 in its ATP-bound conformation, and p23 then interacts with the hsp90 to stabilize the complex. Stepwise assembly experiments have shown that hsp70 and hsp40 first interact with the receptor in an ATP-dependent reaction to produce a receptor·hsp70·hsp40 complex that is “primed” to be activated to the steroid-binding state in a second ATP-dependent step with hsp90, Hop, and p23. Successful use of the five-protein system with other substrates Indicates that it can assemble signal protein-hsp90 heterocomplexes whether the substrate is a receptor, a protein kinase, or a transcription factor. This purified system should facilitate understanding of how eukaryotlc hsp70 and hsp90 work together as essential components of a process that alters the conformations of substrate proteins to states that respond in signal transduction.
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Lepage, P. K., and G. Boulay. "Molecular determinants of TRP channel assembly." Biochemical Society Transactions 35, no. 1 (January 22, 2007): 81–83. http://dx.doi.org/10.1042/bst0350081.
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Calcium channels play important roles in cellular signalling. TRP (transient receptor potential) channels form a superfamily of calcium channels through which Ca2+ enters the cell. TRPs have six transmembrane segments with a putative pore between the fifth and the sixth segments, and assemble in tetrameric complexes to form functional Ca2+ channels. They are thus similar to KV (voltage-gated potassium channel) channels in terms of structure and molecular determinants that promote subunit assembly. In this review, the molecular determinants mediating the assembly of Drosophila TRP, TRPC (TRP canonical), TRPV (TRP vanilloid) and KV channels are described.
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Wu, Glendon S., and Craig H. Bassing. "Inefficient V(D)J recombination underlies monogenic T cell receptor β expression." Proceedings of the National Academy of Sciences 117, no. 31 (July 20, 2020): 18172–74. http://dx.doi.org/10.1073/pnas.2010077117.
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The assembly of T cell receptor (TCR) and immunoglobulin (Ig) genes by V(D)J recombination generates the antigen receptor (AgR) diversity that is vital for adaptive immunity. At most AgR loci, V(D)J recombination is regulated so that only one allele assembles a functional gene, ensuring that nearly every T and B cell expresses a single type, or specificity, of AgR. The genomic organizations of some AgR loci permit the assembly and expression of two distinct genes on each allele; however, this is prevented by undetermined mechanisms. We show that the poor qualities of recombination signal sequences (RSSs) flanking Vβ gene segments suppress the assembly and expression of two distinct TCRβ genes from a single allele. Our data demonstrate that an intrinsic genetic mechanism that stochastically limits Vβ recombination efficiency governs monogenic TCRβ expression, thereby restraining the expression of multiple AgRs on αβ T cells.
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Huang, William Y. C., Qingrong Yan, Wan-Chen Lin, Jean K. Chung, Scott D. Hansen, Sune M. Christensen, Hsiung-Lin Tu, John Kuriyan, and Jay T. Groves. "Phosphotyrosine-mediated LAT assembly on membranes drives kinetic bifurcation in recruitment dynamics of the Ras activator SOS." Proceedings of the National Academy of Sciences 113, no. 29 (July 1, 2016): 8218–23. http://dx.doi.org/10.1073/pnas.1602602113.
Full textAbstract:
The assembly of cell surface receptors with downstream signaling molecules is a commonly occurring theme in multiple signaling systems. However, little is known about how these assemblies modulate reaction kinetics and the ultimate propagation of signals. Here, we reconstitute phosphotyrosine-mediated assembly of extended linker for the activation of T cells (LAT):growth factor receptor-bound protein 2 (Grb2):Son of Sevenless (SOS) networks, derived from the T-cell receptor signaling system, on supported membranes. Single-molecule dwell time distributions reveal two, well-differentiated kinetic species for both Grb2 and SOS on the LAT assemblies. The majority fraction of membrane-recruited Grb2 and SOS both exhibit fast kinetics and single exponential dwell time distributions, with average dwell times of hundreds of milliseconds. The minor fraction exhibits much slower kinetics, extending the dwell times to tens of seconds. Considering this result in the context of the multistep process by which the Ras GEF (guanine nucleotide exchange factor) activity of SOS is activated indicates that kinetic stabilization from the LAT assembly may be important. This kinetic proofreading effect would additionally serve as a stochastic noise filter by reducing the relative probability of spontaneous SOS activation in the absence of receptor triggering. The generality of receptor-mediated assembly suggests that such effects may play a role in multiple receptor proximal signaling processes.
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Nilsson, Eric E., Jacob Stanfield, and Michael K. Skinner. "Interactions between progesterone and tumor necrosis factor-α in the regulation of primordial follicle assembly." Reproduction 132, no. 6 (December 2006): 877–86. http://dx.doi.org/10.1530/rep-06-0045.
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Follicle assembly is the process by which groups or ‘nests’ of oocytes break down to form primordial follicles. The size of the primordial follicle pool is the major determinant of the reproductive lifespan of a female. Previously, progesterone (P4) has been shown to inhibit follicle assembly, while tumor necrosis factor-α (TNFα) has been shown to promote the apoptosis that is necessary for follicle assembly. The present study examines how TNFα and progesterone interact to regulate primordial follicle assembly. Ovaries were collected from newborn rats and placed in organ culture to examine the actions of P4 and TNFα. P4 was found to decrease primordial follicle assembly and increase the percentage of unassembled oocytes both in vitro and in vivo. TNFα treatment did not change the proportion of assembled follicles in cultured ovaries, but blocked the ability of P4 to inhibit follicle assembly. Microarray analysis of the ovarian transcriptome revealed that progesterone treatment of the ovaries altered the expression of 513 genes with 132 only expressed after P4 treatment and 16 only expressed in control ovaries. The majority of genes were up-regulated greater than twofold over control, with a small subset of 16 genes down-regulated. Categories of genes affected by P4 are described including a group of extracellular signaling factors. The progesterone receptors expressed at the time of follicle assembly included the surface membrane progesterone receptors PGRMC1, PGRMC2, and RDA288. The nuclear genomic P4 receptor was not expressed at appreciable levels. Progesterone increased the expression of several genes (TANK, NFκB, Bcl2l1, and Bcl2l2) involved in a signaling pathway that promotes cell survival and inhibits apoptosis. Observations indicate that P4 acts through the surface membrane progesterone receptors to regulate primordial follicle assembly, and that TNFα can override the inhibitory actions of P4 on follicle assembly. A major mechanism involved in the actions of P4 is an increase in cell survival genes and inhibition of the apoptosis pathway. Observations provide insight into the hormonal regulation of primordial follicle assembly and lead to novel approaches to potentially manipulate follicle assembly and reproductive capacity.
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Blount, P., M. M. Smith, and J. P. Merlie. "Assembly intermediates of the mouse muscle nicotinic acetylcholine receptor in stably transfected fibroblasts." Journal of Cell Biology 111, no. 6 (December 1, 1990): 2601–11. http://dx.doi.org/10.1083/jcb.111.6.2601.
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We have used fibroblast clones expressing muscle nicotinic acetylcholine receptor alpha and gamma, and alpha and delta subunits to measure the kinetics of subunit assembly, and to study the properties of the partially assembled products that are formed. We demonstrate by coimmunoprecipitation that assembly intermediates in fibroblasts coexpressing alpha and delta subunits are formed in a time-dependent manner. The alpha and gamma- and the alpha and delta-producing transfected cells form complexes that, when labeled with 125I-alpha-bungarotoxin, migrate in sucrose gradients at 6.3S, a value consistent with a hetero-dimer structure. An additional peak at 8.5S is formed from the alpha and gamma subunits expressed in fibroblasts suggesting that gamma may have more than one binding site for alpha subunit. The stability and specificity of formation of these partially assembled complexes suggests that they are normal intermediates in the assembly of acetylcholine receptor. Comparison of the binding of 125I-alpha-bungarotoxin to intact and detergent-extracted fibroblasts indicate that essentially all of the binding sites are retained in an intracellular pool. The fibroblast delta subunit has the electrophoretic mobility in SDS-PAGE of a precursor that does not contain complex carbohydrates. In addition, alpha gamma and alpha delta complexes had lectin binding properties expected of subunits lacking complex oligosaccharides. Therefore, fibroblasts coexpressing alpha and gamma or alpha and delta subunits produce discrete assembly intermediates that are retained in an intracellular compartment and are not processed by Golgi enzymes.
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MODAN-MOSES, Dalit, Michel JANICOT, John C. McLENITHAN, M. Daniel LANE, and Samuel J. CASELLA. "Expression and function of insulin/insulin-like growth factor I hybrid receptors during differentiation of 3T3-L1 preadipocytes." Biochemical Journal 333, no. 3 (August 1, 1998): 825–31. http://dx.doi.org/10.1042/bj3330825.
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During the assembly of cell surface receptors, insulin proreceptors are sometimes joined to insulin-like growth factor (IGF) receptor precursors to form covalently linked hybrid receptors. To address the biological consequences of hybrid receptor formation, we studied 3T3-L1 cells known to undergo a 50–70-fold increase in insulin binding while maintaining nearly constant levels of IGF-I binding during differentiation from preadipocytes into adipocytes. The presence of insulin/IGF receptor hybrids in 3T3-L1 adipocytes was demonstrated by the immunoprecipitation of phosphorylated receptors and a novel enzyme-linked immunoassay. Hybrid receptor levels were very low in the early stages of differentiation and increased rapidly between days 4 and 6, reaching a level about 100-fold higher in the mature adipocyte. Coincident with the hybrid assembly, the formation of archetypal (α2,β2) IGF receptors decreased. In fully differentiated adipocytes, virtually all of the IGF receptors were in hybrid form. Stimulation by IGF-I of receptors isolated from mature adipocytes caused autophosphorylation of IGF receptor β subunits in hybrid complexes, whereas autophosphorylated IGF holoreceptors were not demonstrable. Insulin and IGF-I were equipotent in stimulating glucose uptake in the differentiated adipocytes, leading to the conclusion that hybrid insulin/IGF receptors can transduce a transmembrane signal when activated by IGF-I. We conclude that hybrid formation constitutes a novel post-translational mechanism whereby increased synthesis of insulin receptors limits the cell surface expression of the homologous IGF receptor. Furthermore, biological actions in 3T3-L1 adipocytes, previously attributed to archetypal IGF receptors, are in fact mediated through hybrid receptors.
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Goodwin, Stewart, Tobias J. Tuthill, Armando Arias, Richard A. Killington, and David J. Rowlands. "Foot-and-Mouth Disease Virus Assembly: Processing of Recombinant Capsid Precursor by Exogenous Protease Induces Self-Assembly of Pentamers In Vitro in a Myristoylation-Dependent Manner." Journal of Virology 83, no. 21 (August 26, 2009): 11275–82. http://dx.doi.org/10.1128/jvi.01263-09.
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ABSTRACT The assembly of foot-and-mouth disease virus (FMDV) particles is poorly understood. In addition, there are important differences in the antigenic and receptor binding properties of virus assembly and dissociation intermediates, and these also remain unexplained. We have established an experimental model in which the antigenicity, receptor binding characteristics, and in vitro assembly of capsid precursor can be studied entirely from purified components. Recombinant capsid precursor protein (P1 region) was expressed in E scherichia coli as myristoylated or unmyristoylated protein. The protein sedimented in sucrose gradients at 5S and reacted with monoclonal antibodies which recognize conformational or linear antigen determinants on the virion surface. In addition, it bound the integrin αvβ6, a cellular receptor for FMDV, indicating that unprocessed recombinant capsid precursor is both structurally and antigenically similar to native virus capsid. These characteristics were not dependent on the presence of 2A at the C terminus but were altered by N-terminal myristoylation and in mutant precursors which lacked VP4. Proteolytic processing of myristoylated precursor by recombinant FMDV 3Cpro in vitro induced a shift in sedimentation from 5S to 12S, indicating assembly into pentameric capsid subunits. Nonmyristoylated precursor still assembled into higher-order structures after processing with 3Cpro, but these particles sedimented in sucrose gradients at approximately 17S. In contrast, mutant precursors lacking VP4 were antigenically distinct, were unable to form pentamers, and had reduced capacity for binding integrin receptor. These studies demonstrate the utility of recombinant capsid precursor protein for investigating the initial stages of assembly of FMDV and other picornaviruses.
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Shim, Jaegal, Tohru Umemura, Erika Nothstein, and Christopher Rongo. "The Unfolded Protein Response Regulates Glutamate Receptor Export from the Endoplasmic Reticulum." Molecular Biology of the Cell 15, no. 11 (November 2004): 4818–28. http://dx.doi.org/10.1091/mbc.e04-02-0108.
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α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors mediate the majority of excitatory signaling in the CNS, and the functional properties and subcellular fate of these receptors depend on receptor subunit composition. Subunit assembly is thought to occur in the endoplasmic reticulum (ER), although we are just beginning to understand the underlying mechanism. Here we examine the trafficking of Caenorhabditis elegans glutamate receptors through the ER. Our data indicate that neurons require signaling by the unfolded protein response (UPR) to move GLR-1, GLR-2, and GLR-5 subunits out of the ER and through the secretory pathway. In contrast, other neuronal transmembrane proteins do not require UPR signaling for ER exit. The requirement for the UPR pathway is cell type and age dependent: impairment for receptor trafficking increases as animals age and does not occur in all neurons. Expression of XBP-1, a component of the UPR pathway, is elevated in neurons during development. Our results suggest that UPR signaling is a critical step in neural function that is needed for glutamate receptor assembly and secretion.
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Young, Brent M., Elaine Nguyen, Matthew A. J. Chedrawe, Jan K. Rainey, and Denis J. Dupré. "Differential Contribution of Transmembrane Domains IV, V, VI, and VII to Human Angiotensin II Type 1 Receptor Homomer Formation." Journal of Biological Chemistry 292, no. 8 (January 17, 2017): 3341–50. http://dx.doi.org/10.1074/jbc.m116.750380.
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G protein-coupled receptors (GPCRs) play an important role in drug therapy and represent one of the largest families of drug targets. The angiotensin II type 1 receptor (AT1R) is notable as it has a central role in the treatment of cardiovascular disease. Blockade of AT1R signaling has been shown to alleviate hypertension and improve outcomes in patients with heart failure. Despite this, it has become apparent that our initial understanding of AT1R signaling is oversimplified. There is considerable evidence to suggest that AT1R signaling is highly modified in the presence of receptor-receptor interactions, but there is very little structural data available to explain this phenomenon even with the recent elucidation of the AT1R crystal structure. The current study investigates the involvement of transmembrane domains in AT1R homomer assembly with the goal of identifying hydrophobic interfaces that contribute to receptor-receptor affinity. A recently published crystal structure of the AT1R was used to guide site-directed mutagenesis of outward-facing hydrophobic residues within the transmembrane region of the AT1R. Bioluminescence resonance energy transfer was employed to analyze how receptor mutation affects the assembly of AT1R homomers with a specific focus on hydrophobic residues. Mutations within transmembrane domains IV, V, VI, and VII had no effect on angiotensin-mediated β-arrestin1 recruitment; however, they exhibited differential effects on the assembly of AT1R into oligomeric complexes. Our results demonstrate the importance of hydrophobic amino acids at the AT1R transmembrane interface and provide the first glimpse of the requirements for AT1R complex assembly.
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Cicchetti, Gregor, Philip G. Allen, and Michael Glogauer. "Chemotactic Signaling Pathways in Neutrophils: from Receptor to Actin Assembly." Critical Reviews in Oral Biology & Medicine 13, no. 3 (May 2002): 220–28. http://dx.doi.org/10.1177/154411130201300302.
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In this review, we present an overview of the signaling elements between neutrophil chemotactic receptors and the actin cytoskeleton that drives cell motility. From receptor-ligand interactions, activation of heterotrimeric G-proteins, their downstream effectors PLC and PI-3 kinase, the activation of small GTPases of the Rho family, and their regulation of particular cytoskeletal regulatory proteins, we describe pathways specific to the chemotaxing neutrophil and elements documented to be important for neutrophil function.
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Lopez, Angel, Timothy Hercus, Guido Hansen, Joanna Woodcock, Barbara McClure, Frank Stomski, William McKinstry, and Michael Parker Parker. "The Structure of the GM-CSF Receptor Ternary Complex Reveals a New Mode of Cytokine Receptor Activation." Blood 110, no. 11 (November 16, 2007): 88. http://dx.doi.org/10.1182/blood.v110.11.88.88.
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Abstract Granulocyte-macrophage colony stimulating factor (GM-CSF) is a pleiotropic cytokine that controls the production and function of blood cells, is deregulated in multiple diseases such as asthma, arthritis and leukaemia yet offers therapeutic value in Crohn’s disease and as an adjuvant in anti-cancer therapy. Its receptors are heterodimers consisting of a ligand-specific alpha subunit and a beta subunit which is critical for signalling and is shared with the interleukin (IL)-3 and IL-5 receptors. The latter have also been implicated in pathologies such as acute myeloid leukaemia and allergic inflammation respectively. Despite the clear involvement of this family of receptors in human diseases their three dimensional structures in complex with the cognate ligand is not known and the mechanism by which they signal has remained an enigma. In particular it has baffled scientists that the membrane proximal domains of the beta subunit are 120A apart, too big a distance to allow transphosphorylation of the receptors by their associated JAK-2 kinases and receptor activation. We report here the structure of the human GM-CSF/GM-CSF receptor ternary complex and its assembly into hexamers (comprising 2 molecules of GM-CSF, alpha subunits and beta subunits each) and into unexpected dodecamers or higher order complexes. The dodecamer arrangement allows the interaction of two hexamers through a distinct site 4 which is composed of both alpha and beta subunits. Importantly, mutagenesis of the GM-CSF receptor at the dodecamer interface revealed that whilst site 4 is not involved in high or low affinity binding of ligand it is critical for receptor activation and signalling. This novel form of receptor assembly likely applies also to the IL-3 and IL-5 receptors, providing a structural basis for understanding cytokine receptor activation and for the development of novel therapeutics.
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Crooke-Rosado, Jonathan L., Sara C. Diaz-Mendez, Yamil E. Claudio-Roman, Nilsa M. Rivera, and Maria A. Sosa. "De novo assembly of the freshwater prawn Macrobrachium carcinus brain transcriptome for identification of potential targets for antibody development." PLOS ONE 16, no. 4 (April 9, 2021): e0249801. http://dx.doi.org/10.1371/journal.pone.0249801.
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Crustaceans are major constituents of aquatic ecosystems and, as such, changes in their behavior and the structure and function of their bodies can serve as indicators of alterations in their immediate environment, such as those associated with climate change and anthropogenic contamination. We have used bioinformatics and a de novo transcriptome assembly approach to identify potential targets for developing specific antibodies to serve as nervous system function markers for freshwater prawns of the Macrobrachium spp. Total RNA was extracted from brain ganglia of Macrobrachium carcinus freshwater prawns and Illumina Next Generation Sequencing was performed using an Eel Pond mRNA Seq Protocol to construct a de novo transcriptome. Sequencing yielded 97,202,662 sequences: 47,630,546 paired and 1,941,570 singletons. Assembly with Trinity resulted in 197,898 assembled contigs from which 30,576 were annotated: 9,600 by orthology, 17,197 by homology, and 3,779 by transcript families. We looked for glutamate receptors contigs, due to their main role in crustacean excitatory neurotransmission, and found 138 contigs related to ionotropic receptors, 32 related to metabotropic receptors, and 18 to unidentified receptors. After performing multiple sequence alignments within different biological organisms and antigenicity analysis, we were able to develop antibodies for prawn AMPA ionotropic glutamate receptor 1, metabotropic glutamate receptor 1 and 4, and ionotropic NMDA glutamate receptor subunit 2B, with the expectation that the availability of these antibodies will help broaden knowledge regarding the underlying structural and functional mechanisms involved in prawn behavioral responses to environmental impacts. The Macrobrachium carcinus brain transcriptome can be an important tool for examining changes in many other nervous system molecules as a function of developmental stages, or in response to particular conditions or treatments.
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Paulson, H. L., A. F. Ross, W. N. Green, and T. Claudio. "Analysis of early events in acetylcholine receptor assembly." Journal of Cell Biology 113, no. 6 (June 15, 1991): 1371–84. http://dx.doi.org/10.1083/jcb.113.6.1371.
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Mammalian cell lines expressing nicotinic acetylcholine receptor (AChR) subunit cDNAs from Torpedo californica were used to study early events in AChR assembly. To test the hypothesis that individual subunits form homooligomeric intermediates before assembling into alpha 2 beta gamma delta pentamers, we analyzed the sedimentation on sucrose density gradients of each subunit expressed separately in cell lines. We have shown previously that the acute temperature sensitivity of Torpedo AChR subunit assembly is due, in part, to misfolding of the polypeptide chains (Paulson, H.L., and T. Claudio. 1990. J. Cell Biol. 110:1705-1717). We use this phenomenon to further analyze putative assembly-competent intermediates. In nonionic detergent at an assembly-permissive temperature, the majority of alpha, beta, gamma, and delta subunits sediment neither as 3-4S monomers nor as 9S complexes, but rather as 6S species whether synthesized in fibroblasts, myoblasts, or differentiated myosyncytia. Several results indicate that the 6S species are complexes comprised predominantly of incorrectly folded subunit polypeptides. The complexes represent homoaggregates which form rapidly within the cell, are stable to mild SDS treatment and, in the case of alpha, contain some disulfide-linked subunits. The coprecipitation of alpha subunit with BiP or GRP78, a resident protein of the ER, further indicates that at least some of these internally sequestered subunits also associated with an endogenous protein implicated in protein folding. The majority of subunits expressed in these cell lines appear to be aggregates of subunits which are not assembly intermediates and are not assembly-competent. The portion which migrates as monomer, in contrast, appears to be the fraction which is assembly competent. This fraction increases at temperatures more permissive for assembly, further indicating the importance of the monomer as the precursor to assembly of alpha 2 beta gamma delta pentamers.
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Jayawickreme, S. P., W. N. Green, and T. Claudio. "Cyclic AMP-regulated AChR assembly is independent of AChR subunit phosphorylation by PKA." Journal of Cell Science 107, no. 6 (June 1, 1994): 1641–51. http://dx.doi.org/10.1242/jcs.107.6.1641.
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Forskolin treatment of cells expressing Torpedo acetylcholine receptors leads to enhanced assembly efficiency of subunits, which correlates with increased phosphorylation of the gamma subunit. To determine the role of the two potential protein kinase A sites of the gamma subunit in receptor assembly, cell lines expressing different mutant receptors were established. Mouse fibroblast cell lines stably expressing wild-type Torpedo acetylcholine receptor alpha, beta, delta subunits plus one of three gamma subunit mutations (S353A, S354A, or S353,354A) were established to identify the protein kinase A phosphorylation sites of gamma in vivo, and to determine if increased phosphorylation of the gamma subunit leads to enhanced expression of receptors. We found that both serines (353, 354) in gamma are phosphorylated in vivo by protein kinase A, however, phosphorylation of either or both of these sites does not lead to increased assembly efficiency. We established a cell line expressing alpha, beta, and gamma(S353,354A) subunits only (no delta), and found that the presence of delta (or its phosphorylation) is also not necessary for the observed stimulation by forskolin. alpha beta gamma, alpha gamma, and beta gamma associations were stimulated by forskolin but alpha beta and alpha delta interactions were not. These data imply that the presence of gamma is necessary for forskolin action. We postulate that forskolin may stimulate acetylcholine receptor expression through a cellular protein that is involved in the folding and/or assembly of protein complexes, and that forskolin may regulate the action of such a protein through phosphorylation.
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Eckey, Maren, Wei Hong, Maria Papaioannou, and Aria Baniahmad. "The Nucleosome Assembly Activity of NAP1 Is Enhanced by Alien." Molecular and Cellular Biology 27, no. 10 (March 5, 2007): 3557–68. http://dx.doi.org/10.1128/mcb.01106-06.
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ABSTRACT The assembly of nucleosomes into chromatin is essential for the compaction of DNA and inactivation of the DNA template to modulate and repress gene expression. The nucleosome assembly protein 1, NAP1, assembles nucleosomes independent of DNA synthesis and was shown to enhance coactivator-mediated gene expression, suggesting a role for NAP1 in transcriptional regulation. Here, we show that Alien, known to harbor characteristics of a corepressor of nuclear hormone receptors such as of the vitamin D receptor (VDR), binds in vivo and in vitro to NAP1 and modulates its activity by enhancing NAP1-mediated nucleosome assembly on DNA. Furthermore, Alien reduces the accessibility of the histones H3 and H4 for NAP1-promoted assembly reaction. This indicates that Alien sustains and reinforces the formation of nucleosomes. Employing deletion mutants of Alien suggests that different regions of Alien are involved in enhancement of NAP1-mediated nucleosome assembly and in inhibiting the accessibility of the histones H3 and H4. In addition, we provide evidence that Alien is associated with chromatin and with micrococcus nuclease-prepared nucleosome fractions and interacts with the histones H3 and H4. Furthermore, chromatin immunoprecipitation and reimmunoprecipitation experiments suggest that NAP1 and Alien localize to the endogenous CYP24 promoter in vivo, a VDR target gene. Based on these findings, we present here a novel pathway linking corepressor function with nucleosome assembly activity.
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Nieves, Daniel J., Elvis Pandzic, Sachith D. Gunasinghe, Jesse Goyette, Dylan M. Owen, J. Justin Gooding, and Katharina Gaus. "The T cell receptor displays lateral signal propagation involving non-engaged receptors." Nanoscale 14, no. 9 (2022): 3513–26. http://dx.doi.org/10.1039/d1nr05855j.
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TCR-CD3 signal propagation is probed by super-resolution microscopy and nano-clustered TCR ligands. TCR-CD3 clusters exceeded the ligand cluster boundaries, requiring multivalent interactions facilitated by TCR-CD3 phosphorylation for assembly.
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Delos Santos, Ralph Christian, Stephen Bautista, Stefanie Lucarelli, Leslie N. Bone, Roya M. Dayam, John Abousawan, Roberto J. Botelho, and Costin N. Antonescu. "Selective regulation of clathrin-mediated epidermal growth factor receptor signaling and endocytosis by phospholipase C and calcium." Molecular Biology of the Cell 28, no. 21 (October 15, 2017): 2802–18. http://dx.doi.org/10.1091/mbc.e16-12-0871.
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Clathrin-mediated endocytosis is a major regulator of cell-surface protein internalization. Clathrin and other proteins assemble into small invaginating structures at the plasma membrane termed clathrin-coated pits (CCPs) that mediate vesicle formation. In addition, epidermal growth factor receptor (EGFR) signaling is regulated by its accumulation within CCPs. Given the diversity of proteins regulated by clathrin-mediated endocytosis, how this process may distinctly regulate specific receptors is a key question. We examined the selective regulation of clathrin-dependent EGFR signaling and endocytosis. We find that perturbations of phospholipase Cγ1 (PLCγ1), Ca2+, or protein kinase C (PKC) impair clathrin-mediated endocytosis of EGFR, the formation of CCPs harboring EGFR, and EGFR signaling. Each of these manipulations was without effect on the clathrin-mediated endocytosis of transferrin receptor (TfR). EGFR and TfR were recruited to largely distinct clathrin structures. In addition to control of initiation and assembly of CCPs, EGF stimulation also elicited a Ca2+- and PKC-dependent reduction in synaptojanin1 recruitment to clathrin structures, indicating broad control of CCP assembly by Ca2+ signals. Hence EGFR elicits PLCγ1-calcium signals to facilitate formation of a subset of CCPs, thus modulating its own signaling and endocytosis. This provides evidence for the versatility of CCPs to control diverse cellular processes.
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Jefford, Gregory, and Ronald R. Dubreuil. "Receptor Clustering Drives Polarized Assembly of Ankyrin." Journal of Biological Chemistry 275, no. 36 (September 2000): 27726–32. http://dx.doi.org/10.1074/jbc.m004959200.
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Park, Sang-Youn, Peter P. Borbat, Gabriela Gonzalez-Bonet, Jaya Bhatnagar, Abiola M. Pollard, Jack H. Freed, Alexandrine M. Bilwes, and Brian R. Crane. "Reconstruction of the chemotaxis receptor–kinase assembly." Nature Structural & Molecular Biology 13, no. 5 (April 23, 2006): 400–407. http://dx.doi.org/10.1038/nsmb1085.
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