The Molecular Basis of the Interaction of Cyclophilin A with α‐Synuclein. Issue 14 (29th January 2020)

• Record Type: Journal Article
• Authors: Favretto, Filippo; Baker, Jeremy D.; Strohäker, Timo; Andreas, Loren B.; Blair, Laura J.; Becker, Stefan; Zweckstetter, Markus
• Is Part Of: Angewandte Chemie international edition. Volume 59:Issue 14(2020)
• Page Start: 5643
• Page End: 5646
• Publication Date: 2020-01-29
• Subjects: cyclophilin -- Parkinson's disease -- proline isomerization -- protein structure -- α-synuclein; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201914878
• Languages: English
• ISSNs: 1433-7851

Abstract

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 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. Abstract : The high‐resolution structure of the PreNAC region of α‐synuclein in complex with the peptidylprolyl isomerase cyclophilin A provides a novel entry point for the modulation of α‐synuclein‐related neurotoxicity. The A53E mutation of α‐synuclein, which causes early‐onset Parkinson's disease, weakens the interaction of α‐synuclein with cyclophilin A.