Статті в журналах: "Chaperone; fibril formation; phosphorylation"

1

Mitra, Gopa, Suvroma Gupta, Asim Poddar, and Bhabatarak Bhattacharyya. "MAP2c prevents arachidonic acid-induced fibril formation of tau: Role of chaperone activity and phosphorylation." Biophysical Chemistry 205 (October 2015): 16–23. http://dx.doi.org/10.1016/j.bpc.2015.06.003.

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2

Selig, Emily E., Courtney O. Zlatic, Dezerae Cox, Yee-Foong Mok, Paul R. Gooley, Heath Ecroyd та Michael D. W. Griffin. "N- and C-terminal regions of αB-crystallin and Hsp27 mediate inhibition of amyloid nucleation, fibril binding, and fibril disaggregation". Journal of Biological Chemistry 295, № 29 (16 травня 2020): 9838–54. http://dx.doi.org/10.1074/jbc.ra120.012748.

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Small heat-shock proteins (sHSPs) are ubiquitously expressed molecular chaperones that inhibit amyloid fibril formation; however, their mechanisms of action remain poorly understood. sHSPs comprise a conserved α-crystallin domain flanked by variable N- and C-terminal regions. To investigate the functional contributions of these three regions, we compared the chaperone activities of various constructs of human αB-crystallin (HSPB5) and heat-shock 27-kDa protein (Hsp27, HSPB1) during amyloid formation by α-synuclein and apolipoprotein C-II. Using an array of approaches, including thioflavin T fluorescence assays and sedimentation analysis, we found that the N-terminal region of Hsp27 and the terminal regions of αB-crystallin are important for delaying amyloid fibril nucleation and for disaggregating mature apolipoprotein C-II fibrils. We further show that the terminal regions are required for stable fibril binding by both sHSPs and for mediating lateral fibril–fibril association, which sequesters preformed fibrils into large aggregates and is believed to have a cytoprotective function. We conclude that although the isolated α-crystallin domain retains some chaperone activity against amyloid formation, the flanking domains contribute additional and important chaperone activities, both in delaying amyloid formation and in mediating interactions of sHSPs with amyloid aggregates. Both these chaperone activities have significant implications for the pathogenesis and progression of diseases associated with amyloid deposition, such as Parkinson's and Alzheimer's diseases.

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3

Ecroyd, Heath, Sarah Meehan, Joseph Horwitz, J. Andrew Aquilina, Justin L. P. Benesch, Carol V. Robinson, Cait E. Macphee та John A. Carver. "Mimicking phosphorylation of αB-crystallin affects its chaperone activity". Biochemical Journal 401, № 1 (11 грудня 2006): 129–41. http://dx.doi.org/10.1042/bj20060981.

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αB-crystallin is a member of the sHsp (small heat-shock protein) family that prevents misfolded target proteins from aggregating and precipitating. Phosphorylation at three serine residues (Ser19, Ser45 and Ser59) is a major post-translational modification that occurs to αB-crystallin. In the present study, we produced recombi-nant proteins designed to mimic phosphorylation of αB-crystallin by incorporating a negative charge at these sites. We employed these mimics to undertake a mechanistic and structural invest-igation of the effect of phosphorylation on the chaperone activity of αB-crystallin to protect against two types of protein misfolding, i.e. amorphous aggregation and amyloid fibril assembly. We show that mimicking phosphorylation of αB-crystallin results in more efficient chaperone activity against both heat-induced and reduc-tion-induced amorphous aggregation of target proteins. Mimick-ing phosphorylation increased the chaperone activity of αB-crystallin against one amyloid-forming target protein (κ-casein), but decreased it against another (ccβ-Trp peptide). We observed that both target protein identity and solution (buffer) conditions are critical factors in determining the relative chaperone ability of wild-type and phosphorylated αB-crystallins. The present study provides evidence for the regulation of the chaperone activity of αB-crystallin by phosphorylation and indicates that this may play an important role in alleviating the pathogenic effects associated with protein conformational diseases.

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4

Nakata, Yui, Yuuto Kitazaki, Hitomi Kanaoka, Erika Shingen, Rina Uehara, Kunihiro Hongo, Yasushi Kawata, and Tomohiro Mizobata. "Formation of Fibrils by the Periplasmic Molecular Chaperone HdeB from Escherichia coli." International Journal of Molecular Sciences 23, no. 21 (October 31, 2022): 13243. http://dx.doi.org/10.3390/ijms232113243.

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The molecular chaperones HdeA and HdeB of the Escherichia coli (E. coli) periplasm protect client proteins from acid denaturation through a unique mechanism that utilizes their acid denatured states to bind clients. We previously demonstrated that the active, acid-denatured form of HdeA is also prone to forming inactive, amyloid fibril-like aggregates in a pH-dependent, reversible manner. In this study, we report that HdeB also displays a similar tendency to form fibrils at low pH. HdeB fibrils were observed at pH < 3 in the presence of NaCl. Similar to HdeA, HdeB fibrils could be resolubilized by a simple shift to neutral pH. In the case of HdeB, however, we found that after extended incubation at low pH, HdeB fibrils were converted into a form that could not resolubilize at pH 7. Fresh fibrils seeded from these “transformed” fibrils were also incapable of resolubilizing at pH 7, suggesting that the transition from reversible to irreversible fibrils involved a specific conformational change that was transmissible through fibril seeds. Analyses of fibril secondary structure indicated that HdeB fibrils retained significant alpha helical content regardless of the conditions under which fibrils were formed. Fibrils that were formed from HdeB that had been treated to remove its intrinsic disulfide bond also were incapable of resolubilizing at pH 7, suggesting that certain residual structures that are retained in acid-denatured HdeB are important for this protein to recover its soluble state from the fibril form.

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5

Raman, Bakthisaran, Tadato Ban, Miyo Sakai, Saloni Y. Pasta, Tangirala Ramakrishna, Hironobu Naiki, Yuji Goto та Ch Mohan Rao. "αB-crystallin, a small heat-shock protein, prevents the amyloid fibril growth of an amyloid β-peptide and β2-microglobulin". Biochemical Journal 392, № 3 (6 грудня 2005): 573–81. http://dx.doi.org/10.1042/bj20050339.

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αB-crystallin, a small heat-shock protein, exhibits molecular chaperone activity. We have studied the effect of αB-crystallin on the fibril growth of the Aβ (amyloid β)-peptides Aβ-(1–40) and Aβ-(1–42). αB-crystallin, but not BSA or hen egg-white lysozyme, prevented the fibril growth of Aβ-(1–40), as revealed by thioflavin T binding, total internal reflection fluorescence microscopy and CD spectroscopy. Comparison of the activity of some mutants and chimaeric α-crystallins in preventing Aβ-(1–40) fibril growth with their previously reported chaperone ability in preventing dithiothreitol-induced aggregation of insulin suggests that there might be both common and distinct sites of interaction on α-crystallin involved in the prevention of amorphous aggregation of insulin and fibril growth of Aβ-(1–40). αB-crystallin also prevents the spontaneous fibril formation (without externally added seeds) of Aβ-(1–42), as well as the fibril growth of Aβ-(1–40) when seeded with the Aβ-(1–42) fibril seed. Sedimentation velocity measurements show that αB-crystallin does not form a stable complex with Aβ-(1–40). The mechanism by which it prevents the fibril growth differs from the known mechanism by which it prevents the amorphous aggregation of proteins. αB-crystallin binds to the amyloid fibrils of Aβ-(1–40), indicating that the preferential interaction of the chaperone with the fibril nucleus, which inhibits nucleation-dependent polymerization of amyloid fibrils, is the mechanism that is predominantly involved. We found that αB-crystallin prevents the fibril growth of β2-microglobulin under acidic conditions. It also retards the depolymerization of β2-microglobulin fibrils, indicating that it can interact with the fibrils. Our study sheds light on the role of small heat-shock proteins in protein conformational diseases, particularly in Alzheimer's disease.

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6

Kulig, Melissa, та Heath Ecroyd. "The small heat-shock protein αB-crystallin uses different mechanisms of chaperone action to prevent the amorphous versus fibrillar aggregation of α-lactalbumin". Biochemical Journal 448, № 3 (21 листопада 2012): 343–52. http://dx.doi.org/10.1042/bj20121187.

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Анотація:

Stress conditions can destabilize proteins, promoting them to unfold and adopt intermediately folded states. Partially folded protein intermediates are unstable and prone to aggregation down off-folding pathways leading to the formation of either amorphous or amyloid fibril aggregates. The sHsp (small heat-shock protein) αB-crystallin acts as a molecular chaperone to prevent both amorphous and fibrillar protein aggregation; however, the precise molecular mechanisms behind its chaperone action are incompletely understood. To investigate whether the chaperone activity of αB-crystallin is dependent upon the form of aggregation (amorphous compared with fibrillar), bovine α-lactalbumin was developed as a model target protein that could be induced to aggregate down either off-folding pathway using comparable buffer conditions. Thus when α-lactalbumin was reduced it aggregated amorphously, whereas a reduced and carboxymethylated form aggregated to form amyloid fibrils. Using this model, αB-crystallin was shown to be a more efficient chaperone against amorphously aggregating α-lactalbumin than when it aggregated to form fibrils. Moreover, αB-crystallin forms high molecular mass complexes with α-lactalbumin to prevent its amorphous aggregation, but prevents fibril formation via weak transient interactions. Thus, the conformational stability of the protein intermediate, which is a precursor to aggregation, plays a critical role in modulating the chaperone mechanism of αB-crystallin.

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7

Akbari, Ali, Fatemeh Bamdad, and Jianping Wu. "Chaperone-like food components: from basic concepts to food applications." Food & Function 9, no. 7 (2018): 3597–609. http://dx.doi.org/10.1039/c7fo01902e.

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The significance of chaperones in preventing protein aggregation including amyloid fibril formation has been extensively documented in the biological field, but there is limited research on the potential effect of chaperone-like molecules on food protein functionality and food quality.

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8

Abelein, Axel, Astrid Gräslund та Jens Danielsson. "Zinc as chaperone-mimicking agent for retardation of amyloid β peptide fibril formation". Proceedings of the National Academy of Sciences 112, № 17 (30 березня 2015): 5407–12. http://dx.doi.org/10.1073/pnas.1421961112.

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Metal ions have emerged to play a key role in the aggregation process of amyloid β (Aβ) peptide that is closely related to the pathogenesis of Alzheimer’s disease. A detailed understanding of the underlying mechanistic process of peptide–metal interactions, however, has been challenging to obtain. By applying a combination of NMR relaxation dispersion and fluorescence kinetics methods we have investigated quantitatively the thermodynamic Aβ–Zn2+ binding features as well as how Zn2+ modulates the nucleation mechanism of the aggregation process. Our results show that, under near-physiological conditions, substoichiometric amounts of Zn2+ effectively retard the generation of amyloid fibrils. A global kinetic profile analysis reveals that in the absence of zinc Aβ40 aggregation is driven by a monomer-dependent secondary nucleation process in addition to fibril-end elongation. In the presence of Zn2+, the elongation rate is reduced, resulting in reduction of the aggregation rate, but not a complete inhibition of amyloid formation. We show that Zn2+ transiently binds to residues in the N terminus of the monomeric peptide. A thermodynamic analysis supports a model where the N terminus is folded around the Zn2+ ion, forming a marginally stable, short-lived folded Aβ40 species. This conformation is highly dynamic and only a few percent of the peptide molecules adopt this structure at any given time point. Our findings suggest that the folded Aβ40–Zn2+ complex modulates the fibril ends, where elongation takes place, which efficiently retards fibril formation. In this conceptual framework we propose that zinc adopts the role of a minimal antiaggregation chaperone for Aβ40.

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9

Xu, Li-Qiong, Si Wu, Alexander K. Buell, Samuel I. A. Cohen, Li-Jun Chen, Wan-Hui Hu, Sarah A. Cusack, et al. "Influence of specific HSP70 domains on fibril formation of the yeast prion protein Ure2." Philosophical Transactions of the Royal Society B: Biological Sciences 368, no. 1617 (May 5, 2013): 20110410. http://dx.doi.org/10.1098/rstb.2011.0410.

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Ure2p is the protein determinant of the Saccharomyces cerevisiae prion state [ URE3 ]. Constitutive overexpression of the HSP70 family member SSA1 cures cells of [ URE3 ]. Here, we show that Ssa1p increases the lag time of Ure2p fibril formation in vitro in the presence or absence of nucleotide. The presence of the HSP40 co-chaperone Ydj1p has an additive effect on the inhibition of Ure2p fibril formation, whereas the Ydj1p H34Q mutant shows reduced inhibition alone and in combination with Ssa1p. In order to investigate the structural basis of these effects, we constructed and tested an Ssa1p mutant lacking the ATPase domain, as well as a series of C-terminal truncation mutants. The results indicate that Ssa1p can bind to Ure2p and delay fibril formation even in the absence of the ATPase domain, but interaction of Ure2p with the substrate-binding domain is strongly influenced by the C-terminal lid region. Dynamic light scattering, quartz crystal microbalance assays, pull-down assays and kinetic analysis indicate that Ssa1p interacts with both native Ure2p and fibril seeds, and reduces the rate of Ure2p fibril elongation in a concentration-dependent manner. These results provide new insights into the structural and mechanistic basis for inhibition of Ure2p fibril formation by Ssa1p and Ydj1p.

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10

Tanaka, Naoki, Ryoji Tanaka, Mutsumi Tokuhara, Shigeru Kunugi, Yin-Fai Lee та Daizo Hamada. "Amyloid Fibril Formation and Chaperone-like Activity of Peptides from αA-Crystallin†". Biochemistry 47, № 9 (березень 2008): 2961–67. http://dx.doi.org/10.1021/bi701823g.

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11

Sanders, Henry M., Blagojce Jovcevski, John A. Carver та Tara L. Pukala. "The molecular chaperone β-casein prevents amorphous and fibrillar aggregation of α-lactalbumin by stabilisation of dynamic disorder". Biochemical Journal 477, № 3 (11 лютого 2020): 629–43. http://dx.doi.org/10.1042/bcj20190638.

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Deficits in protein homeostasis (proteostasis) are typified by the partial unfolding or misfolding of native proteins leading to amorphous or fibrillar aggregation, events that have been closely associated with diseases including Alzheimer's and Parkinson's diseases. Molecular chaperones are intimately involved in maintaining proteostasis, and their mechanisms of action are in part dependent on the morphology of aggregation-prone proteins. This study utilised native ion mobility–mass spectrometry to provide molecular insights into the conformational properties and dynamics of a model protein, α-lactalbumin (α-LA), which aggregates in an amorphous or amyloid fibrillar manner controlled by appropriate selection of experimental conditions. The molecular chaperone β-casein (β-CN) is effective at inhibiting amorphous and fibrillar aggregation of α-LA at sub-stoichiometric ratios, with greater efficiency against fibril formation. Analytical size-exclusion chromatography demonstrates the interaction between β-CN and amorphously aggregating α-LA is stable, forming a soluble high molecular weight complex, whilst with fibril-forming α-LA the interaction is transient. Moreover, ion mobility–mass spectrometry (IM-MS) coupled with collision-induced unfolding (CIU) revealed that α-LA monomers undergo distinct conformational transitions during the initial stages of amorphous (order to disorder) and fibrillar (disorder to order) aggregation. The structural heterogeneity of monomeric α-LA during fibrillation is reduced in the presence of β-CN along with an enhancement in stability, which provides a potential means for preventing fibril formation. Together, this study demonstrates how IM-MS and CIU can investigate the unfolding of proteins as well as examine transient and dynamic protein–chaperone interactions, and thereby provides detailed insight into the mechanism of chaperone action and proteostasis mechanisms.

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12

Rekas, Agata, Christopher G. Adda, J. Andrew Aquilina, Kevin J. Barnham, Margaret Sunde, Denise Galatis, Nicholas A. Williamson та ін. "Interaction of the Molecular Chaperone αB-Crystallin with α-Synuclein: Effects on Amyloid Fibril Formation and Chaperone Activity". Journal of Molecular Biology 340, № 5 (липень 2004): 1167–83. http://dx.doi.org/10.1016/j.jmb.2004.05.054.

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13

Elias, Abigail K., Mark R. Wilson, John A. Carver, and Ian F. Musgrave. "The Extracellular Molecular Chaperone Clusterin Inhibits Amyloid Fibril Formation and Suppresses Cytotoxicity Associated with Semen-Derived Enhancer of Virus Infection (SEVI)." Cells 11, no. 20 (October 17, 2022): 3259. http://dx.doi.org/10.3390/cells11203259.

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Clusterin is a glycoprotein present at high concentrations in many extracellular fluids, including semen. Its increased expression accompanies disorders associated with extracellular amyloid fibril accumulation such as Alzheimer’s disease. Clusterin is an extracellular molecular chaperone which prevents the misfolding and amorphous and amyloid fibrillar aggregation of a wide variety of unfolding proteins. In semen, amyloid fibrils formed from a 39-amino acid fragment of prostatic acid phosphatase, termed Semen-derived Enhancer of Virus Infection (SEVI), potentiate HIV infectivity. In this study, clusterin potently inhibited the in vitro formation of SEVI fibrils, along with dissociating them. Furthermore, clusterin reduced the toxicity of SEVI to pheochromocytoma-12 cells. In semen, clusterin may play an important role in preventing SEVI amyloid fibril formation, in dissociating SEVI fibrils and in mitigating their enhancement of HIV infection.

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14

Yamamoto, Hanae, Naoya Fukui, Mayuka Adachi, Eiichi Saiki, Anna Yamasaki, Rio Matsumura, Daichi Kuroyanagi, Kunihiro Hongo, Tomohiro Mizobata та Yasushi Kawata. "Human Molecular Chaperone Hsp60 and Its Apical Domain Suppress Amyloid Fibril Formation of α-Synuclein". International Journal of Molecular Sciences 21, № 1 (19 грудня 2019): 47. http://dx.doi.org/10.3390/ijms21010047.

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Heat shock proteins play roles in assisting other proteins to fold correctly and in preventing the aggregation and accumulation of proteins in misfolded conformations. However, the process of aging significantly degrades this ability to maintain protein homeostasis. Consequently, proteins with incorrect conformations are prone to aggregate and accumulate in cells, and this aberrant aggregation of misfolded proteins may trigger various neurodegenerative diseases, such as Parkinson’s disease. Here, we investigated the possibilities of suppressing α-synuclein aggregation by using a mutant form of human chaperonin Hsp60, and a derivative of the isolated apical domain of Hsp60 (Hsp60 AD(Cys)). In vitro measurements were used to detect the effects of chaperonin on amyloid fibril formation, and interactions between Hsp60 proteins and α-synuclein were probed by quartz crystal microbalance analysis. The ability of Hsp60 AD(Cys) to suppress α-synuclein intracellular aggregation and cytotoxicity was also demonstrated. We show that Hsp60 mutant and Hsp60 AD(Cys) both effectively suppress α-synuclein amyloid fibril formation, and also demonstrate for the first time the ability of Hsp60 AD(Cys) to function as a mini-chaperone inside cells. These results highlight the possibility of using Hsp60 AD as a method of prevention and treatment of neurodegenerative diseases.

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15

Gong, Weibin, Wanhui Hu, Linan Xu, Huiwen Wu, Si Wu, Hong Zhang, Jinfeng Wang, Gary W. Jones, and Sarah Perrett. "The C-terminal GGAP motif of Hsp70 mediates substrate recognition and stress response in yeast." Journal of Biological Chemistry 293, no. 46 (September 18, 2018): 17663–75. http://dx.doi.org/10.1074/jbc.ra118.002691.

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The allosteric coupling of the highly conserved nucleotide- and substrate-binding domains of Hsp70 has been studied intensively. In contrast, the role of the disordered, highly variable C-terminal region of Hsp70 remains unclear. In many eukaryotic Hsp70s, the extreme C-terminal EEVD motif binds to the tetratricopeptide-repeat domains of Hsp70 co-chaperones. Here, we discovered that the TVEEVD sequence of Saccharomyces cerevisiae cytoplasmic Hsp70 (Ssa1) functions as a SUMO-interacting motif. A second C-terminal motif of ∼15 amino acids between the α-helical lid and the extreme C terminus, previously identified in bacterial and eukaryotic organellar Hsp70s, is known to enhance chaperone function by transiently interacting with folding clients. Using structural analysis, interaction studies, fibril formation assays, and in vivo functional assays, we investigated the individual contributions of the α-helical bundle and the C-terminal disordered region of Ssa1 in the inhibition of fibril formation of the prion protein Ure2. Our results revealed that although the α-helical bundle of the Ssa1 substrate-binding domain (SBDα) does not directly bind to Ure2, the SBDα enhances the ability of Hsp70 to inhibit fibril formation. We found that a 20-residue C-terminal motif in Ssa1, containing GGAP and GGAP-like tetrapeptide repeats, can directly bind to Ure2, the Hsp40 co-chaperone Ydj1, and α-synuclein, but not to the SUMO-like protein SMT3 or BSA. Deletion or substitution of the Ssa1 GGAP motif impaired yeast cell tolerance to temperature and cell-wall damage stress. This study highlights that the C-terminal GGAP motif of Hsp70 is important for substrate recognition and mediation of the heat shock response.

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16

Kim, Soohyun, Eunsook Shin, Hana Im, and Kyunghee Lee. "Expression of Chaperone-Synuclein Fusion Proteins and Their Regulatory Effects on Amyloid Fibril Formation." Bulletin of the Korean Chemical Society 36, no. 11 (October 4, 2015): 2780–83. http://dx.doi.org/10.1002/bkcs.10546.

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17

Miyawaki, Shiori, Yumi Uemura, Kunihiro Hongo, Yasushi Kawata, and Tomohiro Mizobata. "Acid-denatured small heat shock protein HdeA from Escherichia coli forms reversible fibrils with an atypical secondary structure." Journal of Biological Chemistry 294, no. 5 (December 10, 2018): 1590–601. http://dx.doi.org/10.1074/jbc.ra118.005611.

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The periplasmic small heat shock protein HdeA from Escherichia coli is inactive under normal growth conditions (at pH 7) and activated only when E. coli cells are subjected to a sudden decrease in pH, converting HdeA into an acid-denatured active state. Here, using in vitro fibrillation assays, transmission EM, atomic-force microscopy, and CD analyses, we found that when HdeA is active as a molecular chaperone, it is also capable of forming inactive aggregates that, at first glance, resemble amyloid fibrils. We noted that the molecular chaperone activity of HdeA takes precedence over fibrillogenesis under acidic conditions, as the presence of denatured substrate protein was sufficient to suppress HdeA fibril formation. Further experiments suggested that the secondary structure of HdeA fibrils deviates somewhat from typical amyloid fibrils and contains α-helices. Strikingly, HdeA fibrils that formed at pH 2 were immediately resolubilized by a simple shift to pH 7 and from there could regain molecular chaperone activity upon a return to pH 1. HdeA, therefore, provides an unusual example of a “reversible” form of protein fibrillation with an atypical secondary structure composition. The competition between active assistance of denatured polypeptides (its “molecular chaperone” activity) and the formation of inactive fibrillary deposits (its “fibrillogenic” activity) provides a unique opportunity to probe the relationship among protein function, structure, and aggregation in detail.

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18

Castano, E. M., F. Prelli, T. Wisniewski, A. Golabek, R. A. Kumar, C. Soto та B. Frangione. "Fibrillogenesis in Alzheimer's disease of amyloid β peptides and apolipoprotein E". Biochemical Journal 306, № 2 (1 березня 1995): 599–604. http://dx.doi.org/10.1042/bj3060599.

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Анотація:

A central event in Alzheimer's disease is the conformational change from normally circulating soluble amyloid beta peptides (A beta) and tau proteins into amyloid fibrils, in the form of senile plaques and neurofibrillary tangles respectively. The apolipoprotein E (apoE) gene locus has recently been associated with late-onset Alzheimer's disease. It is not know whether apoE plays a direct role in the pathogenesis of the disease. In the present work we have investigated whether apoE can affect the known spontaneous in vitro formation of amyloid-like fibrils by synthetic A beta analogues using a thioflavine-T assay for fibril formation, electron microscopy and Congo Red staining. Our results show that, under the conditions used, apoE directly promotes amyloid fibril formation, increasing both the rate of fibrillogenesis and the total amount of amyloid formed. ApoE accelerated fibril formation of both wild-type A beta-(1-40) and A beta-(1-40A), an analogue created by the replacement of valine with alanine at residue 18, which alone produces few amyloid-like fibrils. However, apoE produced only a minimal effect on A beta-(1-40Q), found in the Dutch variant of Alzheimer's disease. When recombinant apoE isoforms were used, apoE4 was more efficient than apoE3 at enhancing amyloid formation. These in vitro observations support the hypothesis that apoE acts as a pathological chaperone, promoting the beta-pleated-sheet conformation of soluble A beta into amyloid fibres, and provide a possible explanation for the association of the apoE4 genetic isoform with Alzheimer's disease.

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19

Willander, Hanna, Erik Hermansson, Jan Johansson, and Jenny Presto. "BRICHOS domain associated with lung fibrosis, dementia and cancer - a chaperone that prevents amyloid fibril formation?" FEBS Journal 278, no. 20 (July 5, 2011): 3893–904. http://dx.doi.org/10.1111/j.1742-4658.2011.08209.x.

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20

THOMSON, Christy A., and Vettai S. ANANTHANARAYANAN. "Structure–function studies on Hsp47: pH-dependent inhibition of collagen fibril formation in vitro." Biochemical Journal 349, no. 3 (July 25, 2000): 877–83. http://dx.doi.org/10.1042/bj3490877.

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Hsp47, a 47kDa heat shock protein whose expression level parallels that of collagen, has been regarded as a collagen-specific molecular chaperone. Studies from other laboratories have established the association of Hsp47 with the nascent as well as the triple-helical procollagen molecule in the endoplasmic reticulum and its dissociation from procollagen in the Golgi. One of several roles suggested for Hsp47 in collagen biosynthesis is the prevention of aggregation of procollagen in the endoplasmic reticulum. However, no experimental evidence has been available to verify this suggestion. In the present study we have followed the aggregation of mature triple-helical collagen molecules into fibrils by using turbidimetric measurements in the absence and presence of Hsp47. In the pH range 6–7, fibril formation of type I collagen, as monitored by turbidimetry, proceeds with a lag of approx. 10min and levels off by approx. 60min. The addition of Hsp47 at pH 7 effectively inhibits fibril formation at and above a 1:1 molar ratio of Hsp47 to triple-helical collagen. This inhibition is markedly pH-dependent, being significantly diminished at pH 6. CD and fluorescence spectral data of Hsp47 in the pH range 4.2–7.4 reveal a significant alteration in its structure at pH values below 6.2, with a decrease in α-helix and an increase in β-structure. This conformational change is likely to be the basis of the decreased binding of Hsp47 to collagen in vitro at pH 6.3 as well as its inability to inhibit collagen fibril formation at this pH. Our results also provide a functional assay for Hsp47 that can be used in studies on collagen and Hsp47 interactions.

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21

Marvastizadeh, Narges, Bahareh Dabirmanesh, Reza H. Sajedi та Khosro Khajeh. "Anti-amyloidogenic effect of artemin on α-synuclein". Biological Chemistry 401, № 10 (25 вересня 2020): 1143–51. http://dx.doi.org/10.1515/hsz-2019-0446.

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Abstractα-Synuclein fibrillation is now regarded as a major pathogenic process in Parkinson’s disease and its proteinaceous deposits are also detected in other neurological disorders including Alzheimer's disease. Therefore anti-amyloidegenic compounds may delay or prevent the progression of synucleinopathies disease. Molecular chaperones are group of proteins which mediate correct folding of proteins by preventing unsuitable interactions which may lead to aggregation. The objective of this study was to investigate the anti-amyloidogenic effect of molecular chaperone artemin on α-synuclein. As the concentration of artemin was increased up to 4 μg/ml, a decrease in fibril formation of α-synuclein was observed using thioflavin T (ThT) fluorescence and congo red (CR) assay. Transmission electron microscopy (TEM) images also demonstrated a reduction in fibrils in the presence of artemin. The secondary structure of α-synuclein was similar to its native form prior to fibrillation when incubated with artemin. A cell-based assay has shown that artemin inhibits α-synuclein aggregation and reduce cytotoxicity, apoptosis and reactive oxygen species (ROS) production. Our results revealed that artemin has efficient chaperon activity for preventing α-synuclein fibril formation and toxicity.

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Ishida, Yoshihito, Hiroshi Kubota, Akitsugu Yamamoto, Akira Kitamura, Hans Peter Bächinger, and Kazuhiro Nagata. "Type I Collagen in Hsp47-null Cells Is Aggregated in Endoplasmic Reticulum and Deficient in N-Propeptide Processing and Fibrillogenesis." Molecular Biology of the Cell 17, no. 5 (May 2006): 2346–55. http://dx.doi.org/10.1091/mbc.e05-11-1065.

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Heat-shock protein of 47 kDa (Hsp47) is a molecular chaperone that recognizes collagen triple helices in the endoplasmic reticulum (ER). Hsp47-knockout mouse embryos are deficient in the maturation of collagen types I and IV, and collagen triple helices formed in the absence of Hsp47 show increased susceptibility to protease digestion. We show here that the fibrils of type I collagen produced by Hsp47-/- cells are abnormally thin and frequently branched. Type I collagen was highly accumulated in the ER of Hsp47-/- cells, and its secretion rate was much slower than that of Hsp47+/+ cells, leading to accumulation of the insoluble aggregate of type I collagen within the cells. Transient expression of Hsp47 in the Hsp47-/- cells restored normal extracellular fibril formation and intracellular localization of type I collagen. Intriguingly, type I collagen with unprocessed N-terminal propeptide (N-propeptide) was secreted from Hsp47-/- cells and accumulated in the extracellular matrix. These results indicate that Hsp47 is required for correct folding and prevention of aggregation of type I collagen in the ER and that this function is indispensable for efficient secretion, processing, and fibril formation of collagen.

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Moszczynski, Alexander J., May Gohar, Kathryn Volkening, Cheryl Leystra-Lantz, Wendy Strong та Michael J. Strong. "Thr175-phosphorylated tau induces pathologic fibril formation via GSK3β-mediated phosphorylation of Thr231 in vitro". Neurobiology of Aging 36, № 3 (березень 2015): 1590–99. http://dx.doi.org/10.1016/j.neurobiolaging.2014.12.001.

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24

Hayashi, Junna, Jennifer Ton, Sparsh Negi, Daniel E. K. M. Stephens, Dean L. Pountney, Thomas Preiss та John A. Carver. "The Effect of Oxidized Dopamine on the Structure and Molecular Chaperone Function of the Small Heat-Shock Proteins, αB-Crystallin and Hsp27". International Journal of Molecular Sciences 22, № 7 (2 квітня 2021): 3700. http://dx.doi.org/10.3390/ijms22073700.

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Oxidation of the neurotransmitter, dopamine (DA), is a pathological hallmark of Parkinson’s disease (PD). Oxidized DA forms adducts with proteins which can alter their functionality. αB-crystallin and Hsp27 are intracellular, small heat-shock molecular chaperone proteins (sHsps) which form the first line of defense to prevent protein aggregation under conditions of cellular stress. In vitro, the effects of oxidized DA on the structure and function of αB-crystallin and Hsp27 were investigated. Oxidized DA promoted the cross-linking of αB-crystallin and Hsp27 to form well-defined dimer, trimer, tetramer, etc., species, as monitored by SDS-PAGE. Lysine residues were involved in the cross-links. The secondary structure of the sHsps was not altered significantly upon cross-linking with oxidized DA but their oligomeric size was increased. When modified with a molar equivalent of DA, sHsp chaperone functionality was largely retained in preventing both amorphous and amyloid fibrillar aggregation, including fibril formation of mutant (A53T) α-synuclein, a protein whose aggregation is associated with autosomal PD. In the main, higher levels of sHsp modification with DA led to a reduction in chaperone effectiveness. In vivo, DA is sequestered into acidic vesicles to prevent its oxidation and, intracellularly, oxidation is minimized by mM levels of the antioxidant, glutathione. In vitro, acidic pH and glutathione prevented the formation of oxidized DA-induced cross-linking of the sHsps. Oxidized DA-modified αB-crystallin and Hsp27 were not cytotoxic. In a cellular context, retention of significant chaperone functionality by mildly oxidized DA-modified sHsps would contribute to proteostasis by preventing protein aggregation (particularly of α-synuclein) that is associated with PD.

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Meehan, Sarah, Tuomas P. J. Knowles, Andrew J. Baldwin, Jeffrey F. Smith, Adam M. Squires, Phillip Clements, Teresa M. Treweek та ін. "Characterisation of Amyloid Fibril Formation by Small Heat-shock Chaperone Proteins Human αA-, αB- and R120G αB-Crystallins". Journal of Molecular Biology 372, № 2 (вересень 2007): 470–84. http://dx.doi.org/10.1016/j.jmb.2007.06.060.

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26

Nagai, Naoko, Masanori Hosokawa, Shigeyoshi Itohara, Eijiro Adachi, Takatoshi Matsushita, Nobuko Hosokawa, and Kazuhiro Nagata. "Embryonic Lethality of Molecular Chaperone Hsp47 Knockout Mice Is Associated with Defects in Collagen Biosynthesis." Journal of Cell Biology 150, no. 6 (September 18, 2000): 1499–506. http://dx.doi.org/10.1083/jcb.150.6.1499.

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Triple helix formation of procollagen after the assembly of three α-chains at the C-propeptide is a prerequisite for refined structures such as fibers and meshworks. Hsp47 is an ER-resident stress inducible glycoprotein that specifically and transiently binds to newly synthesized procollagens. However, the real function of Hsp47 in collagen biosynthesis has not been elucidated in vitro or in vivo. Here, we describe the establishment of Hsp47 knockout mice that are severely deficient in the mature, propeptide-processed form of α1(I) collagen and fibril structures in mesenchymal tissues. The molecular form of type IV collagen was also affected, and basement membranes were discontinuously disrupted in the homozygotes. The homozygous mice did not survive beyond 11.5 days postcoitus (dpc), and displayed abnormally orientated epithelial tissues and ruptured blood vessels. When triple helix formation of type I collagen secreted from cultured cells was monitored by protease digestion, the collagens of Hsp47+/+ and Hsp47+/− cells were resistant, but those of Hsp47−/− cells were sensitive. These results indicate for the first time that type I collagen is unable to form a rigid triple-helical structure without the assistance of molecular chaperone Hsp47, and that mice require Hsp47 for normal development.

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Folmert, Kristin, Malgorzata Broncel, Hans v. Berlepsch, Christopher Hans Ullrich, Mary-Ann Siegert, and Beate Koksch. "Inhibition of peptide aggregation by means of enzymatic phosphorylation." Beilstein Journal of Organic Chemistry 12 (November 18, 2016): 2462–70. http://dx.doi.org/10.3762/bjoc.12.240.

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As is the case in numerous natural processes, enzymatic phosphorylation can be used in the laboratory to influence the conformational populations of proteins. In nature, this information is used for signal transduction or energy transfer, but has also been shown to play an important role in many diseases like tauopathies or diabetes. With the goal of determining the effect of phosphorylation on amyloid fibril formation, we designed a model peptide which combines structural characteristics of α-helical coiled-coils and β-sheets in one sequence. This peptide undergoes a conformational transition from soluble structures into insoluble amyloid fibrils over time and under physiological conditions and contains a recognition motif for PKA (cAMP-dependent protein kinase) that enables enzymatic phosphorylation. We have analyzed the pathway of amyloid formation and the influence of enzymatic phosphorylation on the different states along the conformational transition from random-coil to β-sheet-rich oligomers to protofilaments and on to insoluble amyloid fibrils, and we found a remarkable directing effect from β-sheet-rich structures to unfolded structures in the initial growth phase, in which small oligomers and protofilaments prevail if the peptide is phosphorylated.

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Månsson, Cecilia, Remco T. P. van Cruchten, Ulrich Weininger, Xiaoting Yang, Risto Cukalevski, Paolo Arosio, Christopher M. Dobson та ін. "Conserved S/T Residues of the Human Chaperone DNAJB6 Are Required for Effective Inhibition of Aβ42 Amyloid Fibril Formation". Biochemistry 57, № 32 (19 липня 2018): 4891–902. http://dx.doi.org/10.1021/acs.biochem.8b00353.

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Khodarahmi, Reza, Hosnieh Soori, and Seyyed Arash Karimi. "Chaperone-like activity of heme group against amyloid-like fibril formation by hen egg ovalbumin: Possible mechanism of action." International Journal of Biological Macromolecules 44, no. 1 (January 2009): 98–106. http://dx.doi.org/10.1016/j.ijbiomac.2008.10.011.

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Franco, Aitor, Pablo Gracia, Adai Colom, José D. Camino, José Ángel Fernández-Higuero, Natalia Orozco, Alexander Dulebo та ін. "All-or-none amyloid disassembly via chaperone-triggered fibril unzipping favors clearance of α-synuclein toxic species". Proceedings of the National Academy of Sciences 118, № 36 (30 серпня 2021): e2105548118. http://dx.doi.org/10.1073/pnas.2105548118.

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α-synuclein aggregation is present in Parkinson’s disease and other neuropathologies. Among the assemblies that populate the amyloid formation process, oligomers and short fibrils are the most cytotoxic. The human Hsc70-based disaggregase system can resolve α-synuclein fibrils, but its ability to target other toxic assemblies has not been studied. Here, we show that this chaperone system preferentially disaggregates toxic oligomers and short fibrils, while its activity against large, less toxic amyloids is severely impaired. Biochemical and kinetic characterization of the disassembly process reveals that this behavior is the result of an all-or-none abrupt solubilization of individual aggregates. High-speed atomic force microscopy explicitly shows that disassembly starts with the destabilization of the tips and rapidly progresses to completion through protofilament unzipping and depolymerization without accumulation of harmful oligomeric intermediates. Our data provide molecular insights into the selective processing of toxic amyloids, which is critical to identify potential therapeutic targets against increasingly prevalent neurodegenerative disorders.

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Mahalingam, Sundararajan, Goutham Shankar, Brian P. Mooney, Kamal Singh, Puttur Santhoshkumar та Krishna K. Sharma. "Deletion of Specific Conserved Motifs from the N-Terminal Domain of αB-Crystallin Results in the Activation of Chaperone Functions". International Journal of Molecular Sciences 23, № 3 (20 січня 2022): 1099. http://dx.doi.org/10.3390/ijms23031099.

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Smaller oligomeric chaperones of α-crystallins (αA- and αB-) have received increasing attention due to their improved therapeutic potential in preventing protein aggregating diseases. Our previous study suggested that deleting 54–61 residues from the N-terminal domain (NTD) of αB-crystallin (αBΔ54–61) decreases the oligomer size and increases the chaperone function. Several studies have also suggested that NTD plays a significant role in protein oligomerization and chaperone function. The current study was undertaken to assess the effect of deleting conserved 21–28 residues from the activated αBΔ54–61 (to get αBΔ21–28, Δ54–61) on the structure–function of recombinant αBΔ21–28, Δ54–61. The αBΔ21–28, Δ54–61 mutant shows an 80% reduction in oligomer size and 3- to 25-fold increases in chaperone activity against model substrates when compared to αB-WT. Additionally, the αB∆21–28, ∆54–61 was found to prevent β-amyloid (Aβ1–42) fibril formation in vitro and suppressed Aβ1–42-induced cytotoxicity in ARPE-19 cells in a more effective manner than seen with αB-WT or αB∆54–61. Cytotoxicity and reactive oxygen species (ROS) detection studies with sodium iodate (SI) showed that the double mutant protein has higher anti-apoptotic and anti-oxidative activities than the wild-type or αB∆54–61 in oxidatively stressed cells. Our study shows that the residues 21–28 and 54–61 in αB-crystallin contribute to the oligomerization and modulate chaperone function. The deletion of conserved 21–28 residues further potentiates the activated αBΔ54–61. We propose that increased substrate affinity, altered subunit structure, and assembly leading to smaller oligomers could be the causative factors for the increased chaperone activity of αBΔ21–28, Δ54–61.

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KOBAYASHI, Tsuyoshi, Yoshihito NAKATANI, Toshihiro TANIOKA, Masafumi TSUJIMOTO, Shigeo NAKAJO, Kazuyasu NAKAYA, Makoto MURAKAMI, and Ichiro KUDO. "Regulation of cytosolic prostaglandin E synthase by phosphorylation." Biochemical Journal 381, no. 1 (June 22, 2004): 59–69. http://dx.doi.org/10.1042/bj20040118.

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cPGES [cytosolic PG (prostaglandin) E synthase] is constitutively expressed in various cells and can regulate COX (cyclo-oxygenase)-1-dependent immediate PGE2 generation. In the present study, we found that cPGES underwent serine phosphorylation, which was accelerated transiently after cell activation. Several lines of evidence suggest that a cPGES-activating protein kinase is CK-II (casein kinase II). Recombinant cPGES was phosphorylated directly by and associated with CK-II in vitro, resulting in marked reduction of the Km for the substrate PGH2. In activated cells, cPGES phosphorylation occurred in parallel with increased cPGES enzymic activity and PGE2 production from exogenous and endogenous arachidonic acid, and these processes were facilitated by Hsp90 (heat-shock protein 90), a molecular chaperone that formed a tertiary complex with cPGES and CK-II. Treatment of cells with inhibitors of CK-II and Hsp90 and with a dominant-negative CK-II attenuated the formation of the cPGES–CK-II–Hsp90 complex and attendant cPGES phosphorylation and activation. Mutations of either of two predicted CK-II phosphorylation sites on cPGES (Ser113 and Ser118) abrogated its phosphorylation and activation both in vitro and in vivo. Moreover, the CK-II–Hsp90-mediated activation of cPGES was ameliorated by the p38 mitogen-activated protein kinase inhibitor SB20358 or by the anti-inflammatory glucocorticoid dexamethasone. Taken together, the results of the present study have provided the first evidence that the cellular function of this eicosanoid-biosynthetic enzyme is under the control of a molecular chaperone and its client protein kinase.

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Wennerberg, K., R. Fassler, B. Warmegard, and S. Johansson. "Mutational analysis of the potential phosphorylation sites in the cytoplasmic domain of integrin beta1A. Requirement for threonines 788–789 in receptor activation." Journal of Cell Science 111, no. 8 (April 15, 1998): 1117–26. http://dx.doi.org/10.1242/jcs.111.8.1117.

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To investigate the role of the potential phosphorylation sites in the cytoplasmic domain of integrin beta1A, point mutated variants of the protein were stably expressed in the beta1-deficient cell line GD25. Mutants T777A, Y783F, S785A, and Y795F were fully active in promoting cell adhesion, de novo formation of focal contacts, formation of fibronectin fibrils, and activation of focal adhesion kinase. Thus, phosphorylation of these residues is not required for several basic functions of integrin beta1A. On the other hand, the TT788-9AA mutant, was defective in mediating cell attachment and did not contribute to fibronectin fibril formation. The conformation of the extracellular domain was shifted towards an inactive state as measured by binding of the monoclonal antibody 9EG7. Antibody induced clustering of beta1ATT788-9AA demonstrated that the mutant cytoplasmic part was functional in mediating activation of focal adhesion kinase. Therefore, we conclude that threonines 788–789, which are conserved among most integrin beta subunits, are of critical importance for integrin function due to effects on the extracellular conformation of the receptor.

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Treweek, Teresa M., Heath Ecroyd, Danielle M. Williams, Sarah Meehan, John A. Carver та Mark J. Walker. "Site-Directed Mutations in the C-Terminal Extension of Human αB-Crystallin Affect Chaperone Function and Block Amyloid Fibril Formation". PLoS ONE 2, № 10 (17 жовтня 2007): e1046. http://dx.doi.org/10.1371/journal.pone.0001046.

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Ghahghaei, Arezou, Adeleh Divsalar та Nasim Faridi. "The Effects of Molecular Crowding on the Amyloid Fibril Formation of α-Lactalbumin and the Chaperone Action of α-Casein". Protein Journal 29, № 4 (травень 2010): 257–64. http://dx.doi.org/10.1007/s10930-010-9247-3.

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Shu, Qin, Andrzej M. Krezel, Zachary T. Cusumano, Jerome S. Pinkner, Roger Klein, Scott J. Hultgren, and Carl Frieden. "Solution NMR structure of CsgE: Structural insights into a chaperone and regulator protein important for functional amyloid formation." Proceedings of the National Academy of Sciences 113, no. 26 (June 13, 2016): 7130–35. http://dx.doi.org/10.1073/pnas.1607222113.

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Curli, consisting primarily of major structural subunit CsgA, are functional amyloids produced on the surface ofEscherichia coli, as well as many other enteric bacteria, and are involved in cell colonization and biofilm formation. CsgE is a periplasmic accessory protein that plays a crucial role in curli biogenesis. CsgE binds to both CsgA and the nonameric pore protein CsgG. The CsgG–CsgE complex is the curli secretion channel and is essential for the formation of the curli fibril in vivo. To better understand the role of CsgE in curli formation, we have determined the solution NMR structure of a double mutant of CsgE (W48A/F79A) that appears to be similar to the wild-type (WT) protein in overall structure and function but does not form mixed oligomers at NMR concentrations similar to the WT. The well-converged structure of this mutant has a core scaffold composed of a layer of two α-helices and a layer of three-stranded antiparallel β-sheet with flexible N and C termini. The structure of CsgE fits well into the cryoelectron microscopy density map of the CsgG–CsgE complex. We highlight a striking feature of the electrostatic potential surface in CsgE structure and present an assembly model of the CsgG–CsgE complex. We suggest a structural mechanism of the interaction between CsgE and CsgA. Understanding curli formation can provide the information necessary to develop treatments and therapeutic agents for biofilm-related infections and may benefit the prevention and treatment of amyloid diseases. CsgE could establish a paradigm for the regulation of amyloidogenesis because of its unique role in curli formation.

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Hintermayer, Matthew A., Kathryn Volkening, Alexander J. Moszczynski, Neil Donison, and Michael J. Strong. "Tau protein phosphorylation at Thr 175 initiates fibril formation via accessibility of the N‐terminal phosphatase‐activating domain." Journal of Neurochemistry 155, no. 3 (December 30, 2019): 313–26. http://dx.doi.org/10.1111/jnc.14942.

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Sultan, Abdullah, Bakthisaran Raman, Ch Mohan Rao та Ramakrishna Tangirala. "The Extracellular Chaperone Haptoglobin Prevents Serum Fatty Acid-promoted Amyloid Fibril Formation of β2-Microglobulin, Resistance to Lysosomal Degradation, and Cytotoxicity". Journal of Biological Chemistry 288, № 45 (27 вересня 2013): 32326–42. http://dx.doi.org/10.1074/jbc.m113.498337.

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Wolffe, Elizabeth J., Andrea S. Weisberg, and Bernard Moss. "The Vaccinia Virus A33R Protein Provides a Chaperone Function for Viral Membrane Localization and Tyrosine Phosphorylation of the A36R Protein." Journal of Virology 75, no. 1 (January 1, 2001): 303–10. http://dx.doi.org/10.1128/jvi.75.1.303-310.2001.

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ABSTRACT The products of the A33R and A36R genes of vaccinia virus are incorporated into the membranes of intracellular enveloped virions (IEV). When extracts of cells that had been infected with vaccinia virus and labeled with H3 32PO4 were immunoprecipitated with antibodies against the A33R protein, two prominent bands were resolved. The moderately and more intensely labeled bands were identified as phosphorylated A33R and A36R proteins, respectively. The immunoprecipitated complex contained disulfide-bonded dimers of A33R protein that were noncovalently linked to A36R protein. Biochemical analysis indicated that the two proteins were phosphorylated predominantly on serine residues, with lesser amounts on threonines. The A36R protein was also phosphorylated on tyrosine, as determined by specific binding to an anti-phosphotyrosine antibody. Serine phosphorylation and A33R-A36R protein complex formation occurred even when virus assembly was blocked at an early stage with the drug rifampin. Tyrosine phosphorylation was selectively reduced in cells infected with F13L or A34R gene deletion mutants that were impaired in the membrane-wrapping step of IEV formation. In addition, tyrosine phosphorylation was specifically inhibited in cells infected with an A33R deletion mutant that still formed IEV. Immunofluorescence and immunoelectron microscopy indicated that in the absence of the A33R protein, the A36R protein was localized in Golgi membranes but not in IEV. In the absence of the A36R protein, however, the A33R protein still localized to IEV membranes. These studies together with others suggest that the A33R protein guides the A36R protein to the IEV membrane, where it subsequently becomes tyrosine phosphorylated as a signal for actin tail formation.

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Shimazaki, Masashi, Kazuto Nakamura, Isao Kii, Takeshi Kashima, Norio Amizuka, Minqi Li, Mitsuru Saito, et al. "Periostin is essential for cardiac healingafter acute myocardial infarction." Journal of Experimental Medicine 205, no. 2 (January 21, 2008): 295–303. http://dx.doi.org/10.1084/jem.20071297.

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Acute myocardial infarction (AMI) is a common and lethal heart disease, and the recruitment of fibroblastic cells to the infarct region is essential for the cardiac healing process. Although stiffness of the extracellular matrix in the infarct myocardium is associated with cardiac healing, the molecular mechanism of cardiac healing is not fully understood. We show that periostin, which is a matricellular protein, is important for the cardiac healing process after AMI. The expression of periostin protein was abundant in the infarct border of human and mouse hearts with AMI. We generated periostin−/− mice and found no morphologically abnormal cardiomyocyte phenotypes; however, after AMI, cardiac healing was impaired in these mice, resulting in cardiac rupture as a consequence of reduced myocardial stiffness caused by a reduced number of α smooth muscle actin–positive cells, impaired collagen fibril formation, and decreased phosphorylation of FAK. These phenotypes were rescued by gene transfer of a spliced form of periostin. Moreover, the inhibition of FAK or αv-integrin, which blocked the periostin-promoted cell migration, revealed that αv-integrin, FAK, and Akt are involved in periostin signaling. Our novel findings show the effects of periostin on recruitment of activated fibroblasts through FAK-integrin signaling and on their collagen fibril formation specific to healing after AMI.

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Morimoto, Daichi, and Masahiro Shirakawa. "The evolving world of ubiquitin: transformed polyubiquitin chains." Biomolecular Concepts 7, no. 3 (June 1, 2016): 157–67. http://dx.doi.org/10.1515/bmc-2016-0009.

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AbstractThe regulation of diverse cellular events by proteins that have undergone post-translational modification with ubiquitin is well documented. Ubiquitin can be polymerized and eight types of polyubiquitin chain contribute to the complexity and specificity of the ubiquitin signal. Unexpectedly, recent studies have shown that ubiquitin itself undergoes post-translational modification by acetylation and phosphorylation; moreover, amyloid-like fibrils comprised of polyubiquitin chains have been discovered. Thus, ubiquitin is not only conjugated to substrate proteins, but also modified and transformed itself. Here, we review these novel forms of ubiquitin signal, with a focus on fibril formation of polyubiquitin chains and its underlying biological relevance.

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Sun, Lei, Georg Stoecklin, Susan Van Way, Vania Hinkovska-Galcheva, Ren-Feng Guo, Paul Anderson, and Thomas Shanley. "Protein Phosphatase 2A destabilizes TNF alpha mRNA by dephosphorylating Tristetraprolin (94.8)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S172. http://dx.doi.org/10.4049/jimmunol.178.supp.94.8.

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Abstract Tumor necrosis factor (TNF)-α is a major cytokine produced by alveolar macrophages in response to pathogen associated molecular patterns such as LPS. TNF-α secretion is regulated at both transcriptional and post-transcriptional levels. Post-transcriptional regulation occurs by modulation of TNF-α mRNA stability via the binding of tristetraprolin (TTP) to the AU (adenosine/uridine)-rich elements (AREs) found in the 3’-untranslated region (3’-UTR) of TNF-α transcript. Phosphorylation plays important roles in modulating mRNA stability. Our results show that inhibition of PP2A by okadaic acid or siRNA significantly enhanced the stability of TNF-α mRNA. This result was associated with increased phosphorylation of p38 MAPK and MK-2. PP2A inhibition increased TTP phosphorylation and enhanced complex formation with chaperone protein 14-3-3. A functional consequence of TTP/14-3-3 complex formation appeared to be protection of TTP from dephosphorylation by inhibition of the binding of the catalytic unit of PP2A to phosphorylated TTP. Our data indicates that PP2A regulates TNF-α mRNA stability by modulating the phosphorylation state of members of the p38/MK-2/TTP pathway. This work was supported by grants from the National Institute of Health (7R01GM066839-03, to TPS).

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Liu, Peng, Libo Hou, Min Liu, Xuechuan Xu, Qi Gao, Jiewen Deng, Shasha Xiang, et al. "Phosphoproteomic Analysis of Spiroplasma eriocheiris and Crosstalk with Acetylome Reveals the Role of Post-Translational Modifications in Metabolism." Current Proteomics 17, no. 5 (July 16, 2020): 392–403. http://dx.doi.org/10.2174/1570164617666191017140456.

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Background: Post-translational modifications (PTMs) such as phosphorylation are an essential regulatory mechanism of protein function and associated with a range of biological processes beyond genome and transcriptome. Spiroplasma eriocheiris, a wall-less helical bacterium, is one of the smallest known self-replicating bacteria and a novel pathogen of freshwater crustacean. Methods: To study the physiological characteristics and regulatory mechanism of S. eriocheiris, the protein phosphorylation in the bacterium were systematically investigated by iTRAQ analyzed by LC-MS/MS. Data are available via ProteomeXchange with identifier PXD015055. Results: We identified 465 phosphorylation sites in 246 proteins involved in a broad spectrum of fundamental biological process ranging from regulation of metabolic pathways to protein synthesis. Notably, most proteins in glycolysis and all proteins in the arginine deiminase system were phosphorylated. Meanwhile, the cytoskeleton proteins (Fibril, Mrebs and ET-Tu) were all phosphorylated suggest that the phosphorylation also may play a crucial role in cell skeleton formation. We have got a lot of highly conserved proteins and phosphorylation sites by analysis, and those proteins or phosphorylation sites were mainly participated in glucose metabolism and protein synthesis. Crosstalk analysis with protein-protein interaction networks in relation to phosphorylated proteins and acetylated proteins found that the two PTMs are required for playing crucial roles in many physiological processes in S. eriocheiris. By comparing the relative positions of acetylation versus phosphorylation, we found that the two modifications often found close to proximity on the same protein. Conclusions: The results imply that there is previously unreported hidden role of phosphorylation that define the functional state of Spiroplasma.

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Naeimi, Wesley R., and Tricia R. Serio. "Beyond Amyloid Fibers: Accumulation, Biological Relevance, and Regulation of Higher-Order Prion Architectures." Viruses 14, no. 8 (July 27, 2022): 1635. http://dx.doi.org/10.3390/v14081635.

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The formation of amyloid fibers is associated with a diverse range of disease and phenotypic states. These amyloid fibers often assemble into multi-protofibril, high-order architectures in vivo and in vitro. Prion propagation in yeast, an amyloid-based process, represents an attractive model to explore the link between these aggregation states and the biological consequences of amyloid dynamics. Here, we integrate the current state of knowledge, highlight opportunities for further insight, and draw parallels to more complex systems in vitro. Evidence suggests that high-order fibril architectures are present ex vivo from disease relevant environments and under permissive conditions in vivo in yeast, including but not limited to those leading to prion formation or instability. The biological significance of these latter amyloid architectures or how they may be regulated is, however, complicated by inconsistent experimental conditions and analytical methods, although the Hsp70 chaperone Ssa1/2 is likely involved. Transition between assembly states could form a mechanistic basis to explain some confounding observations surrounding prion regulation but is limited by a lack of unified methodology to biophysically compare these assembly states. Future exciting experimental entryways may offer opportunities for further insight.

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45

Elias, Ruben D., Wen Ma, Rodolfo Ghirlando, Charles D. Schwieters, Vijay S. Reddy, and Lalit Deshmukh. "Proline-rich domain of human ALIX contains multiple TSG101-UEV interaction sites and forms phosphorylation-mediated reversible amyloids." Proceedings of the National Academy of Sciences 117, no. 39 (September 11, 2020): 24274–84. http://dx.doi.org/10.1073/pnas.2010635117.

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Proline-rich domains (PRDs) are among the most prevalent signaling modules of eukaryotes but often unexplored by biophysical techniques as their heterologous recombinant expression poses significant difficulties. Using a “divide-and-conquer” approach, we present a detailed investigation of a PRD (166 residues; ∼30% prolines) belonging to a human protein ALIX, a versatile adaptor protein involved in essential cellular processes including ESCRT-mediated membrane remodeling, cell adhesion, and apoptosis. In solution, the N-terminal fragment of ALIX-PRD is dynamically disordered. It contains three tandem sequentially similar proline-rich motifs that compete for a single binding site on its signaling partner, TSG101-UEV, as evidenced by heteronuclear NMR spectroscopy. Global fitting of relaxation dispersion data, measured as a function of TSG101-UEV concentration, allowed precise quantitation of these interactions. In contrast to the soluble N-terminal portion, the C-terminal tyrosine-rich fragment of ALIX-PRD forms amyloid fibrils and viscous gels validated using dye-binding assays with amyloid-specific probes, congo red and thioflavin T (ThT), and visualized by transmission electron microscopy. Remarkably, fibrils dissolve at low temperatures (2 to 6 °C) or upon hyperphosphorylation with Src kinase. Aggregation kinetics monitored by ThT fluorescence shows that charge repulsion dictates phosphorylation-mediated fibril dissolution and that the hydrophobic effect drives fibril formation. These data illuminate the mechanistic interplay between interactions of ALIX-PRD with TSG101-UEV and polymerization of ALIX-PRD and its central role in regulating ALIX function. This study also demonstrates the broad functional repertoires of PRDs and uncovers the impact of posttranslational modifications in the modulation of reversible amyloids.

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Nerelius, Charlotte, Emily Martin, Siwei Peng, Magnus Gustafsson, Kerstin Nordling, Timothy Weaver, and Jan Johansson. "Mutations linked to interstitial lung disease can abrogate anti-amyloid function of prosurfactant protein C." Biochemical Journal 416, no. 2 (November 12, 2008): 201–9. http://dx.doi.org/10.1042/bj20080981.

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The newly synthesized proSP-C (surfactant protein C precursor) is an integral ER (endoplasmic reticulum) membrane protein with a single metastable polyvaline α-helical transmembrane domain that comprises two-thirds of the mature peptide. More than 20 mutations in the ER-lumenal CTC (C-terminal domain of proSP-C), are associated with ILD (interstitial lung disease), and some of the mutations cause intracellular accumulation of cytotoxic protein aggregates and a corresponding decrease in mature SP-C. In the present study, we showed that: (i) human embryonic kidney cells expressing the ILD-associated mutants proSP-CL188Q and proSP-CΔExon4 accumulate Congo Red-positive amyloid-like inclusions, whereas cells transfected with the mutant proSP-CI73T do not; (ii) transfection of CTC into cells expressing proSP-CL188Q results in a stable CTC–proSP-CL188Q complex, increased proSP-CL188Q half-life and reduced formation of Congo Red-positive deposits; (iii) replacement of the metastable polyvaline transmembrane segment with a stable polyleucine transmembrane segment likewise prevents formation of amyloid-like proSP-CL188Q aggregates; and (iv) binding of recombinant CTC to non-helical SP-C blocks SP-C amyloid fibril formation. These results suggest that CTC can prevent the polyvaline segment of proSP-C from promoting formation of amyloid-like deposits during biosynthesis, by binding to non-helical conformations. Mutations in the Brichos domain of proSP-C may lead to ILD via loss of CTC chaperone function.

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Shelton, Lindsey B., Jeremy D. Baker, Dali Zheng, Leia E. Sullivan, Parth K. Solanki, Jack M. Webster, Zheying Sun, et al. "Hsp90 activator Aha1 drives production of pathological tau aggregates." Proceedings of the National Academy of Sciences 114, no. 36 (August 21, 2017): 9707–12. http://dx.doi.org/10.1073/pnas.1707039114.

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The microtubule-associated protein tau (MAPT, tau) forms neurotoxic aggregates that promote cognitive deficits in tauopathies, the most common of which is Alzheimer’s disease (AD). The 90-kDa heat shock protein (Hsp90) chaperone system affects the accumulation of these toxic tau species, which can be modulated with Hsp90 inhibitors. However, many Hsp90 inhibitors are not blood–brain barrier-permeable, and several present associated toxicities. Here, we find that the cochaperone, activator of Hsp90 ATPase homolog 1 (Aha1), dramatically increased the production of aggregated tau. Treatment with an Aha1 inhibitor, KU-177, dramatically reduced the accumulation of insoluble tau. Aha1 colocalized with tau pathology in human brain tissue, and this association positively correlated with AD progression. Aha1 overexpression in the rTg4510 tau transgenic mouse model promoted insoluble and oligomeric tau accumulation leading to a physiological deficit in cognitive function. Overall, these data demonstrate that Aha1 contributes to tau fibril formation and neurotoxicity through Hsp90. This suggests that therapeutics targeting Aha1 may reduce toxic tau oligomers and slow or prevent neurodegenerative disease progression.

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Kawashima, Toshiyuki, Ying Chun Bao, Yukinori Minoshima, Yasushi Nomura, Tomonori Hatori, Tetsuya Hori, Tatsuo Fukagawa, et al. "A Rac GTPase-Activating Protein, MgcRacGAP, Is a Nuclear Localizing Signal-Containing Nuclear Chaperone in the Activation of STAT Transcription Factors." Molecular and Cellular Biology 29, no. 7 (January 21, 2009): 1796–813. http://dx.doi.org/10.1128/mcb.01423-08.

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ABSTRACT In addition to their pleiotropic functions under physiological conditions, transcription factors STAT3 and STAT5 also have oncogenic activities, but how activated STATs are transported to the nucleus has not been fully understood. Here we show that an MgcRacGAP mutant lacking its nuclear localizing signal (NLS) blocks nuclear translocation of p-STATs both in vitro and in vivo. Unlike wild-type MgcRacGAP, this mutant did not promote complex formation of phosphorylated STATs (p-STATs) with importin α in the presence of GTP-bound Rac1, suggesting that MgcRacGAP functions as an NLS-containing nuclear chaperone. We also demonstrate that mutants of STATs lacking the MgcRacGAP binding site (the strand βb) are hardly tyrosine phosphorylated after cytokine stimulation. Intriguingly, mutants harboring small deletions in the C′-adjacent region (βb-βc loop region) of the strand βb became constitutively active with the enhanced binding to MgcRacGAP. The molecular basis of this phenomenon will be discussed, based on the computer-assisted tertiary structure models of STAT3. Thus, MgcRacGAP functions as both a critical mediator of STAT's tyrosine phosphorylation and an NLS-containing nuclear chaperone of p-STATs.

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Carroll, Matthew, John Dyer, and Wayne S. Sossin. "Serotonin Increases Phosphorylation of Synaptic 4EBP through TOR, but Eukaryotic Initiation Factor 4E Levels Do Not Limit Somatic Cap-Dependent Translation in Aplysia Neurons." Molecular and Cellular Biology 26, no. 22 (September 18, 2006): 8586–98. http://dx.doi.org/10.1128/mcb.00955-06.

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ABSTRACT The target of rapamycin (TOR) plays an important role in memory formation in Aplysia californica. Here, we characterize one of the downstream targets of TOR, the eukaryotic initiation factor 4E (eIF4E) binding protein (4EBP) from Aplysia. Aplysia 4EBP contains the four critical phosphorylation sites regulated by TOR as well as an N-terminal RAIP motif and a C-terminal TOS site. Aplysia 4EBP was hypophosphorylated in synaptosomes, and serotonin addition caused a rapamycin-sensitive increase in 4EBP phosphorylation both in synaptosomes and in isolated neurites. Aplysia 4EBP was regulated in a fashion similar to that of mammalian 4EBPs, binding to eIF4E when dephosphorylated and releasing eIF4E after phosphorylation. Overexpression of 4EBP in the soma of Aplysia neurons caused a specific decrease in cap-dependent translation that was rescued by concomitant overexpression of eIF4E. However, eIF4E overexpression by itself did not increase cap-dependent translation, suggesting that increasing levels of free eIF4E by phosphorylating 4EBP is not important in regulating cap-dependent translation in the cell soma. Total levels of eIF4E were also regulated by 4EBP, suggesting that 4EBP can also act as an eIF4E chaperone. These studies demonstrate the conserved nature of 4EBP regulation and its role in cap-dependent translation and suggest differential roles of 4EBP phosphorylation in the soma and synapse.

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Aragão Gomes, Luis, Valerie Uytterhoeven, Diego Lopez-Sanmartin, Sandra O. Tomé, Thomas Tousseyn, Rik Vandenberghe, Mathieu Vandenbulcke, Christine A. F. von Arnim, Patrik Verstreken, and Dietmar Rudolf Thal. "Maturation of neuronal AD-tau pathology involves site-specific phosphorylation of cytoplasmic and synaptic tau preceding conformational change and fibril formation." Acta Neuropathologica 141, no. 2 (January 11, 2021): 173–92. http://dx.doi.org/10.1007/s00401-020-02251-6.

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