The α-crystallin Chaperones Undergo a Quasi-ordered Co-aggregation Process in Response to Saturating Client Interaction.

Autor: Miller AP; Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR 97239, USA; Vollum Institute, Oregon Health & Science University, Portland, OR 97239, USA; Department of Chemistry, Portland State University, Portland, OR 97201, USA., O'Neill SE; Department of Chemistry, Portland State University, Portland, OR 97201, USA., Lampi KJ; Biomaterial and Biomedical Sciences, Oregon Health & Science University, Portland, OR 97239, USA., Reichow SL; Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR 97239, USA; Vollum Institute, Oregon Health & Science University, Portland, OR 97239, USA; Department of Chemistry, Portland State University, Portland, OR 97201, USA. Electronic address: reichow@ohsu.edu.
Jazyk: angličtina
Zdroj: Journal of molecular biology [J Mol Biol] 2024 Apr 15; Vol. 436 (8), pp. 168499. Date of Electronic Publication: 2024 Feb 23.
DOI: 10.1016/j.jmb.2024.168499
Abstrakt: Small heat shock proteins (sHSPs) are ATP-independent chaperones vital to cellular proteostasis, preventing protein aggregation events linked to various human diseases including cataract. The α-crystallins, αA-crystallin (αAc) and αB-crystallin (αBc), represent archetypal sHSPs that exhibit complex polydispersed oligomeric assemblies and rapid subunit exchange dynamics. Yet, our understanding of how this plasticity contributes to chaperone function remains poorly understood. Using biochemical and biophysical analyses combined with single-particle electron microscopy (EM), we examined structural changes in αAc, αBc and native heteromeric lens α-crystallins (αLc) in their apo-states and at varying degree of chaperone saturation leading to co-aggregation, using lysozyme and insulin as model clients. Quantitative single-particle analysis unveiled a continuous spectrum of oligomeric states formed during the co-aggregation process, marked by significant client-triggered expansion and quasi-ordered elongation of the sHSP oligomeric scaffold, whereby the native cage-like sHSP assembly displays a directional growth to accommodate saturating conditions of client sequestration. These structural modifications culminated in an apparent amorphous collapse of chaperone-client complexes, resulting in the creation of co-aggregates capable of scattering visible light. Intriguingly, these co-aggregates maintain internal morphological features of highly elongated sHSP oligomers with striking resemblance to polymeric α-crystallin species isolated from aged lens tissue. This mechanism appears consistent across αAc, αBc and αLc, albeit with varying degrees of susceptibility to client-induced co-aggregation. Importantly, our findings suggest that client-induced co-aggregation follows a distinctive mechanistic and quasi-ordered trajectory, distinct from a purely amorphous process. These insights reshape our understanding of the physiological and pathophysiological co-aggregation processes of α-crystallins, carrying potential implications for a pathway toward cataract formation.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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