Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 59, Issue 14, Pages 5643-5646Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201914878
Keywords
cyclophilin; Parkinson's disease; proline isomerization; protein structure; alpha-synuclein
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Funding
- NIH/NINDS [R01 NS073899]
- German Science Foundation through an Emmy Noether scholarship [AN 1316/1-1]
- German Science Foundation through Collaborative Research Center 860
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Peptidylprolyl isomerases (PPIases) catalyze cis/trans isomerization of prolines. The PPIase CypA colocalizes with the Parkinson's disease (PD)-associated protein alpha-synuclein in cells and interacts with alpha-synuclein oligomers. Herein, we describe atomic insights into the molecular details of the alpha-synuclein/CypA interaction. NMR spectroscopy shows that CypA catalyzes isomerization of proline 128 in the C-terminal domain of alpha-synuclein. Strikingly, we reveal a second CypA-binding site formed by the hydrophobic sequence (47)GVVHGVATVA(56), termed PreNAC. The 1.38 angstrom crystal structure of the CypA/PreNAC complex displays a contact between alanine 53 of alpha-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 alpha-synuclein with CypA. Our study provides high-resolution insights into the structure of the PD-associated protein alpha-synuclein in complex with the most abundant cellular cyclophilin.
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