Disorder, quasi-order, order: a holistic view of small heat shock proteins

Klevit, Rachel E.; Clouser, Amanda F.; Baughman, Hannah E.E.R.; Woods, C. M.; Janowska, Maria K.; Stone, Natalie L.; Ulmer, Lindsey D; Bush, Matthew J.; Guttman, Miklós

doi:10.1016/j.bpj.2021.11.1222

Cited by 1 publication

(1 citation statement)

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“…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%

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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