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- Title
The Molecular Basis of the Interaction of Cyclophilin A with α‐Synuclein.
- Authors
Favretto, Filippo; Baker, Jeremy D.; Strohäker, Timo; Andreas, Loren B.; Blair, Laura J.; Becker, Stefan; Zweckstetter, Markus
- 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.
- Subjects
ISOMERASES; MOLECULAR interactions; CYCLOPHILINS; PARKINSON'S disease; NUCLEAR magnetic resonance spectroscopy; PROTEIN structure
- Publication
Angewandte Chemie, 2020, Vol 132, Issue 14, p5692
- ISSN
0044-8249
- Publication type
Article
- DOI
10.1002/ange.201914878