The binding of the small heat-shock protein αB-crystallin to fibrils of α-synuclein is driven by entropic forces.

Abstract

Molecular chaperones are key components of the cellular proteostasis network whose role includes the suppression of the formation and proliferation of pathogenic aggregates associated with neurodegenerative diseases. The molecular principles that allow chaperones to recognize misfolded and aggregated proteins remain, however, incompletely understood. To address this challenge, here we probe the thermodynamics and kinetics of the interactions between chaperones and protein aggregates under native solution conditions using a microfluidic platform. We focus on the binding between amyloid fibrils of α-synuclein, associated with Parkinson's disease, to the small heat-shock protein αB-crystallin, a chaperone widely involved in the cellular stress response. We find that αB-crystallin binds to α-synuclein fibrils with high nanomolar affinity and that the binding is driven by entropy rather than enthalpy. Measurements of the change in heat capacity indicate significant entropic gain originates from the disassembly of the oligomeric chaperones that function as an entropic buffer system. These results shed light on the functional roles of chaperone oligomerization and show that chaperones are stored as inactive complexes which are capable of releasing active subunits to target aberrant misfolded species.

• Authors: Tom Scheidt, Jacqueline A Carozza, Carl C Kolbe, Francesco A Aprile, Olga Tkachenko, Mathias M J Bellaiche, Georg Meisl, Quentin A E Peter, Therese W Herling, Samuel Ness, Marta Castellana-Cruz, Justin L P Benesch, Michele Vendruscolo, Christopher M Dobson, Paolo Arosio, Tuomas P J Knowles
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 118 Issue 38 (09 21 2021) ISSN: 1091-6490 [Electronic] United States
• PMID: 34518228 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 the Author(s). Published by PNAS.

Chemical References

• Amyloid
• Heat-Shock Proteins, Small
• Protein Aggregates
• alpha-Crystallin B Chain
• alpha-Synuclein

Topics

• Amyloid (metabolism)
• Entropy
• Heat-Shock Proteins, Small (metabolism)
• Humans
• Parkinson Disease (metabolism)
• Protein Aggregates (physiology)
• Proteostasis (physiology)
• alpha-Crystallin B Chain (metabolism)
• alpha-Synuclein (metabolism)