Journal Article

DZNE-2026-00772

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The Molecular Basis of the Interaction of Cyclophilin A with α‐Synuclein

Favretto, F. (First author)DZNE* ; Baker, J. D. ; Strohäker, T.DZNE* ; Andreas, L. B. ; Blair, L. J. ; Becker, S. ; Zweckstetter, M. (Last author)DZNE*

2020
Wiley-VCH Weinheim

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Please use a persistent id in citations: doi:10.1002/ange.201914878

Abstract: Peptidylprolyl isomerases (PPIases) catalyze cis/trans isomerization of prolines. The PPIase CypA colocalizes with the Parkinson's disease (PD)-associated protein α-synuclein in cells and interacts with α-synuclein oligomers. Herein, we describe atomic insights into the molecular details of the α-synuclein/CypA interaction. NMR spectroscopy shows that CypA catalyzes isomerization of proline 128 in the C-terminal domain of α-synuclein. Strikingly, we reveal a second CypA-binding site formed by the hydrophobic sequence 47GVVHGVATVA56, termed PreNAC. The 1.38 Å crystal structure of the CypA/PreNAC complex displays a contact between alanine 53 of α-synuclein and glutamine 111 in the catalytic pocket of CypA. Mutation of alanine 53 to glutamate, as found in patients with early-onset PD, weakens the interaction of α-synuclein with CypA. Our study provides high-resolution insights into the structure of the PD-associated protein α-synuclein in complex with the most abundant cellular cyclophilin.

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Contributing Institute(s):

1. Translational Structural Biology (AG Zweckstetter)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

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Database coverage:
; DEAL Wiley ; Ebsco Academic Search ; Nationallizenz ; SCOPUS

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