title: The molecular chaperone Hsp90 modulates intermediate steps of amyloid assembly of the Parkinson-related protein alpha-synuclein.
abstract: 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.
authors.affiliation: Institute of Chemistry, University of Graz, Heinrichstrasse 28, A-8010 Graz, Austria. fabio.falsone@uni-graz.at
authors.forename: S Fabio
authors.initials: SF
authors.lastname: Falsone
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Kungl
authors.forename: Angelika
authors.initials: A
authors.lastname: Rek
authors.forename: Roberto
authors.initials: R
authors.lastname: Cappai
authors.forename: Klaus
authors.initials: K
authors.lastname: Zangger
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000682:Amyloid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017510:Protein Folding; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D000682:Amyloid; D018841:HSP90 Heat-Shock Proteins; D051844:alpha-Synuclein; D000255:Adenosine Triphosphate