Falsone SF, Kungl AJ, Rek A, Cappai R, Zangger K

Institute of Chemistry, University of Graz, Heinrichstrasse 28, A-8010 Graz, Austria. fabio.falsone@uni-graz.at

Alpha-synuclein is an intrinsically unstructured protein that binds to membranes, forms fibrils, and is involved in neurodegeneration. We used a reconstituted in vitro system to show that the molecular chaperone Hsp90 influenced alpha-synuclein vesicle binding and amyloid fibril formation, two processes that are tightly coupled to alpha-synuclein folding. Binding of Hsp90 to monomeric alpha-synuclein occurred in the low micromolar range, involving regions of alpha-synuclein that are critical for vesicle binding and amyloidogenesis. As a consequence, both processes were affected. In the absence of ATP, the accumulation of non-amyloid alpha-synuclein oligomers prevailed over fibril formation, whereas ATP favored fibril growth. This suggests that Hsp90 modulates the assembly of alpha-synuclein in an ATP-dependent manner. We propose that Hsp90 affects these folding processes by restricting conformational fluctuations of alpha-synuclein.

Mesh Terms:
Adenosine Triphosphate, Amyloid, HSP90 Heat-Shock Proteins, Humans, Kinetics, Models, Biological, Parkinson Disease, Protein Binding, Protein Folding, alpha-Synuclein

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