The beauty and complexity of the small heat shock proteins: a report on the proceedings of the fourth workshop on small heat shock proteins

Ecroyd, Heath; Bartelt-Kirbach, Britta; Ben‐Zvi, Anat; Bonavita, Raffaella; Bushman, Yevheniia; Casarotto, E.; Cecconi, Ciro; Lau, Wilson Chun Yu; Hibshman, Jonathan D.; Joosten, Joep; Kimonis, Virginia; Klevit, Rachel E.; Liberek, Krzysztof; McMenimen, Kathryn A.; Miwa, Tsukumi; Mogk, Axel; Montepietra, Daniele; Peters, Carsten; Rocchetti, Maria Teresa; Saman, Dominik; Sisto, Angela; Secco, Valentina; Strauch, Annika; Taguchi, Hideki; Tanguay, Mark; Tedesco, B.; Tóth, Melinda E.; Wang, Zihao; Benesch, Justin L. P.; Carra, Serena

doi:10.1007/s12192-023-01360-x

Cited by 2 publications

(5 citation statements)

References 37 publications

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“…sHsps also play a role in promoting the disaggregation of some substrates. The mechanism of the sHsp chaperone function has been challenging to untangle due to their dynamic structure heterogeneity [ 38 , 90 ]. sHsps have a characterized structure that spans from monomers, dimers, and small oligomers up to large heterogeneous oligomers, and in vitro chaperone activity has been observed across all structural conformations [ 24 , 27 , 54 , 91 , 92 ].…”

Section: Discussionmentioning

confidence: 99%

“…Dysfunction in sHsps due to mutations or alterations in the proteostasis network is linked to several diseases including cataracts, myopathies, neuropathies, and cancer [ 1 , 3 , 4 , 23 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ]. sHsps participate in proteostasis by interacting with a large diversity of non-native peptides and proteins to prevent irreversible aggregation [ 4 , 44 , 45 , 46 , 47 , 48 ].…”

Section: Introductionmentioning

confidence: 99%

“…Recent evidence suggests that sHsps actively form complexes in conjunction with substrate binding, and they are importantly implicated in the disaggregation of non-native substrates. Importantly, there is not a single substrate binding site, and sHsps have the capacity to bind up to equal MW of the client [ 36 , 37 , 38 , 46 , 53 , 54 , 55 , 56 , 57 , 58 ].…”

Section: Introductionmentioning

confidence: 99%

“…However, their complex dynamics create technical challenges to studying the structure and mechanism of these proteins, rendering detailed analysis of the structural aspects of sHsps incomplete. Recent studies have indicated that all sHsp domains, the N-and C-terminals along with the ACD, are involved in managing this critical dynamic assembly, which is modulated through a succession of dynamic and weak interactions [8][9][10][11][12][13][14]32,38,74,75]. Disease-related mutations have provided insight into some of the molecular mechanisms of sHsp chaperone activity [13,34,[41][42][43]60,77,78].…”

Section: Introductionmentioning

confidence: 99%

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HspB5 Chaperone Structure and Activity Are Modulated by Chemical-Scale Interactions in the ACD Dimer Interface

Wang,

Teng,

Liu

et al. 2023

IJMS

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Small heat shock proteins (sHsps) are a family of ATP-independent molecular chaperones that function as “holdases” and prevent protein aggregation due to changes in temperature, pH, or oxidation state. sHsps have a conserved α-crystallin domain (ACD), which forms the dimer building block, flanked by variable N- and C-terminal regions. sHsps populate various oligomeric states as a function of their sequestrase activity, and these dynamic structural features allow the proteins to interact with a plethora of cellular substrates. However, the molecular mechanisms of their dynamic conformational assembly and the interactions with various substrates remains unclear. Therefore, it is important to gain insight into the underlying physicochemical properties that influence sHsp structure in an effort to understand their mechanism(s) of action. We evaluated several disease-relevant mutations, D109A, F113Y, R116C, R120G, and R120C, in the ACD of HspB5 for changes to in vitro chaperone activity relative to that of wildtype. Structural characteristics were also evaluated by ANS fluorescence and CD spectroscopy. Our results indicated that mutation Y113F is an efficient holdase, while D109A and R120G, which are found in patients with myofibrillar myopathy and cataracts, respectively, exhibit a large reduction in holdase activity in a chaperone-like light-scattering assay, which indicated alterations in substrate–sHsp interactions. The extent of the reductions in chaperone activities are different among the mutants and specific to the substrate protein, suggesting that while sHsps are able to interact with many substrates, specific interactions provide selectivity for some substrates compared to others. This work is consistent with a model for chaperone activity where key electrostatic interactions in the sHsp dimer provide structural stability and influence both higher-order sHsp interactions and facilitate interactions with substrate proteins that define chaperone holdase activity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

HspB5 Chaperone Structure and Activity Are Modulated by Chemical-Scale Interactions in the ACD Dimer Interface

Wang,

Teng,

Liu

et al. 2023

IJMS

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“…Small heat shock proteins (sHsps) are a ubiquitously expressed, highly conserved class of intracellular molecular chaperones that are characterised by the ability to inhibit aggregation of misfolded proteins in an ATP-independent manner [1,2]. The expression of some sHsps is dramatically upregulated in response to cellular stress, conditions conducive to protein misfolding and aggregation [3,4].…”

Section: Introductionmentioning

confidence: 99%

Single-molecule observations of human small heat shock proteins in complex with aggregation-prone client proteins

Rice,

Marzano,

Cox

et al. 2024

Preprint

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Small heat shock proteins (sHsps) are molecular chaperones that act to prevent the aberrant aggregation of misfolded proteins. Whilst it is widely suggested that sHsps prevent aggregation by binding to misfolded client proteins, the dynamic and heterogeneous nature of sHsps has hindered attempts to establish the mechanistic details of how sHsp-client protein complexes form. Single-molecule approaches have emerged as a powerful tool to investigate dynamic and heterogeneous interactions such as those that can occur between sHsps and their client proteins. Here, we use total internal reflection fluorescence microscopy to observe and characterise the complexes formed between model aggregation-prone client proteins [firefly luciferase (FLUC), rhodanese, and chloride intracellular channel 1 protein (CLIC)], and the human sHsps αB-crystallin (αB-c; HSPB1) and Hsp27 (HSPB5). We show that small (monomeric or dimeric) forms of both αB-c and Hsp27 bind to misfolded or oligomeric forms of the client proteins at early stages of aggregation, resulting in the formation of soluble sHsp-client complexes. Stoichiometric analysis of these complexes revealed that additional αB-c subunits accumulate onto pre-existing sHsp-client complexes to form larger species - this does not occur to the same extent for Hsp27. This indicates that Hsp27-client interactions do not require large complexes to prevent aggregation, and are more transient than those of αB-c. Elucidating these mechanisms of sHsp function is crucial to our understanding of how these molecular chaperones act to inhibit protein aggregation and maintain cellular proteostasis.

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The beauty and complexity of the small heat shock proteins: a report on the proceedings of the fourth workshop on small heat shock proteins

Cited by 2 publications

References 37 publications

HspB5 Chaperone Structure and Activity Are Modulated by Chemical-Scale Interactions in the ACD Dimer Interface

HspB5 Chaperone Structure and Activity Are Modulated by Chemical-Scale Interactions in the ACD Dimer Interface

Single-molecule observations of human small heat shock proteins in complex with aggregation-prone client proteins

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