Mechanism of small heat shock protein client sequestration and induced polydispersity

Adam P. Miller and Steve L. Reichow ()
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Adam P. Miller: Oregon Health and Science University
Steve L. Reichow: Oregon Health and Science University

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract Small heat shock proteins (sHSPs) act as first responders during cellular stress, sequestering destabilized proteins (clients) to prevent aggregation and facilitate refolding or degradation. This critical function, conserved across all life, is linked to proteostasis and protein misfolding diseases. However, the extreme molecular plasticity of sHSP/client complexes has limited mechanistic understanding. Here, we present high-resolution cryo-EM structures of Methanocaldococcus jannaschii sHSP (mjHSP16.5) in apo and multiple client-bound states. The ensemble reveals molecular mechanisms of client sequestration, highlighting cooperative chaperone-client interactions. Client engagement polarizes scaffold stability, promoting higher-order assembly and enhanced sequestration. Higher-order states suggest multiple sHSP/client assembly pathways, including subunit insertion at destabilized geometrical features. These findings provide critical insights into sHSP chaperone function and the interplay between polydispersity and client handling under stress.

Date: 2025
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DOI: 10.1038/s41467-025-58964-3

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