Nature’s molecular sponges: Small heat shock proteins grow into their chaperone roles

Eyles, Stephen J.; Gierasch, Lila M.

doi:10.1073/pnas.0915160107

Cited by 88 publications

(64 citation statements)

References 17 publications

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“…3). The specificity of molecular chaperone is an important and intriguing subject; however, most recent studies indicate that the sHSPs have a broad substrate specificity and can interact with a wide range of proteins (4,15). Similarly, our results demonstrate that NtHSP24.6 protects a very wide range of E. coli cellular proteins from heat denaturation and aggregation.…”

Section: Resultssupporting

confidence: 57%

“…In their native state, they typically exist as multimeric complexes of 8 to 24 or more subunits (19)(20)(21) and each of these complexes is considered to act as a reservoir of sHSP rather than being an active chaperone. Once they are subjected to heat, these oligomeric complexes undergo a conformational changes to form either larger oligomers or dimers, which display chaperone activity (4,15). In this work, a hexa-histidine tag was attached to the N-terminus, which likely hindered the formation of a higher order quaternary structure, i.e.…”

Section: Resultsmentioning

confidence: 99%

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Tobacco mitochondrial small heat shock protein NtHSP24.6 adopts a dimeric configuration and has a broad range of substrates

Kim

Yu²,

Park³

et al. 2011

BMB Reports

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There is a broad range of different small heat shock proteins (sHSPs) that have diverse structural and functional characteristics. To better understand the functional role of mitochondrial sHSP, NtHSP24.6 was expressed in Escherichia coli with a hexahistidine tag and purified. The protein was analyzed by non-denaturing PAGE, chemical cross-linking and size exclusion chromatography and the H6NtHSP24.6 protein was found to form a dimer in solution. The in vitro functional analysis of H6NtHSP24.6 using firefly luciferase and citrate synthase demonstrated that this protein displays typical molecular chaperone activity. When cell lysates of E. coli were heated after the addition of H6NtHSP24.6, a broad range of proteins from 10 to 160 kD in size remained in the soluble state. These results suggest that NtHSP24.6 forms a dimer and can function as a molecular chaperone to protect a diverse range of proteins from thermal aggregation. [BMB reports 2011; 44(12): 816-820]

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Section: Resultssupporting

confidence: 57%

Section: Resultsmentioning

confidence: 99%

Tobacco mitochondrial small heat shock protein NtHSP24.6 adopts a dimeric configuration and has a broad range of substrates

Kim

Yu²,

Park³

et al. 2011

BMB Reports

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“…The molecular basis of Hsp42 function in promoting its association with misfolded proteins is largely unknown. It has been previously suggested that the versatile dynamic oligomers formed by Hsp42 might function as a scaffold that promotes protein-protein interactions (Eyles and Gierasch, 2010;Haslbeck et al, 2005;Sun and MacRae, 2005). Based on this hypothesis, we propose that the structurally abnormal features of the proteosome induced by the presence of Rpn5ΔC, promote an acute stress reaction, inducing the formation of higher Hsp42 oligomers, which further accumulate into MMP inclusions in the IPOD.…”

Section: Discussionmentioning

confidence: 95%

Proteasome storage granules are transiently associated with the insoluble protein deposit in Saccharomyces cerevisiae

Peters

Karmon

Miodownik

et al. 2016

Journal of Cell Science

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Proteasome storage granules (PSGs) are created in yeast as part of an extensive and programmed reorganization of proteins into reversible assemblies upon carbon source depletion. Here, we demonstrate that cells distinguish dysfunctional proteasomes from PSGs on the cytosolic insoluble protein deposit (IPOD). Furthermore, we provide evidence that this is a general mechanism for the reorganization of additional proteins into reversible assemblies. Our study expands the roles of the IPOD, which might serve not only as the specific depository for amyloidogenic and misfolded proteins, but also as a potential hub from which proteins are directed to distinct cellular compartments. These findings therefore provide a framework for understanding how cells discriminate between intact and abnormal proteins under stress conditions to ensure that only structurally 'correct' proteins are deployed.

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“…Discussion sHsps constitute an ancient and efficient protective system capable of binding unfolding proteins under conditions of proteotoxic stress (54)(55)(56). The majority of sHsps, among them also human αB, show an unusual structural plasticity (21).…”

Section: N-terminal Flexibility Facilitates Client Reactivation By Thmentioning

confidence: 99%

Regulated structural transitions unleash the chaperone activity of αB-crystallin

Peschek

Braun

Rohrberg

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

157

169

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The small heat shock protein αB-crystallin is an oligomeric molecular chaperone that binds aggregation-prone proteins. As a component of the proteostasis system, it is associated with cataract, neurodegenerative diseases, and myopathies. The structural determinants for the regulation of its chaperone function are still largely elusive. Combining different experimental approaches, we show that phosphorylation-induced destabilization of intersubunit interactions mediated by the N-terminal domain (NTD) results in the remodeling of the oligomer ensemble with an increase in smaller, activated species, predominantly 12-mers and 6-mers. Their 3D structures determined by cryo-electron microscopy and biochemical analyses reveal that the NTD in these species gains flexibility and solvent accessibility. These modulated properties are accompanied by an increase in chaperone activity in vivo and in vitro and a more efficient cooperation with the heat shock protein 70 system in client folding. Thus, the modulation of the structural flexibility of the NTD, as described here for phosphorylation, appears to regulate the chaperone activity of αB-crystallin rendering the NTD a conformational sensor for nonnative proteins.olecular chaperones share the ability to bind nonnative, aggregation-prone polypeptides and assist their folding and assembly (1-3). Among these, the small heat shock protein (sHsp) αB-crystallin (also HspB5) is one of the major constituents of the vertebrate eye lens where it functions both as a chaperone and structural protein (4, 5). In nonlenticular tissues, αB-crystallin (αB) participates in sustaining cellular proteostasis. The involvement in neurodegenerative diseases (6, 7), multiple sclerosis (8), myopathies (9), as well as in cell cycle control, apoptosis, and cancer (10, 11) underlines its importance for cellular proteostasis.αB exhibits a tripartite organization (Fig. 1A) with a central α-crystallin domain (ACD) flanked by an N-terminal domain (NTD) and a short C-terminal extension (CTE) (12, 13). The ACD forms stable dimers (14-16) that further assemble into higher-order oligomers via interactions mediated by the NTD and CTE (17)(18)(19). αB forms dynamic populations of multimers with a variable number of subunits (20,21). Structural studies indicate that the variety of oligomeric states including a symmetric 24-mer (22) is created by addition of subunits to (or subtraction from) existing oligomers (17, 18). As for many other sHsps (23), the polydispersity of αB is coupled to spontaneous subunit exchange of yet undetermined units. αB quaternary dynamics was attributed to fluctuations of the intersubunit contacts mediated by the C-terminal IXI motif (24). However, given its involvement in oligomer formation, the NTD must also play a decisive role.In general, sHsps including αB recognize aggregation-prone, partially unfolded substrates (4, 25, 26) and keep them in a refolding-competent state (27, 28). The substrate binding sites of sHsps have not been defined yet. Recent studies suggest the involvement ...

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Nature’s molecular sponges: Small heat shock proteins grow into their chaperone roles

Cited by 88 publications

References 17 publications

Tobacco mitochondrial small heat shock protein NtHSP24.6 adopts a dimeric configuration and has a broad range of substrates

Tobacco mitochondrial small heat shock protein NtHSP24.6 adopts a dimeric configuration and has a broad range of substrates

Proteasome storage granules are transiently associated with the insoluble protein deposit in Saccharomyces cerevisiae

Regulated structural transitions unleash the chaperone activity of αB-crystallin

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