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The Molecular Basis of the Interaction of Cyclophilin A with α‐Synuclein
Author(s) -
Favretto Filippo,
Baker Jeremy D.,
Strohäker Timo,
Andreas Loren B.,
Blair Laura J.,
Becker Stefan,
Zweckstetter Markus
Publication year - 2020
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201914878
Subject(s) - cypa , cyclophilin a , peptidylprolyl isomerase , cyclophilin , isomerase , cis trans isomerases , chemistry , alanine , fkbp , stereochemistry , biochemistry , biophysics , crystallography , amino acid , biology , enzyme , microbiology and biotechnology , gene
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 47 GVVHGVATVA 56 , 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.