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The PPIase CypA colocalizes with the Parkinson's disease (PD)\u2010associated protein \u03b1\u2010synuclein in cells and interacts with \u03b1\u2010synuclein oligomers. Herein, we describe atomic insights into the molecular details of the \u03b1\u2010synuclein\/CypA interaction. NMR spectroscopy shows that CypA catalyzes isomerization of proline\u2005128 in the C\u2010terminal domain of \u03b1\u2010synuclein. Strikingly, we reveal a second CypA\u2010binding site formed by the hydrophobic sequence <jats:sup>47<\/jats:sup>GVVHGVATVA<jats:sup>56<\/jats:sup>, termed PreNAC. The 1.38\u2005\u00c5 crystal structure of the CypA\/PreNAC complex displays a contact between alanine\u200553 of \u03b1\u2010synuclein and glutamine\u2005111 in the catalytic pocket of CypA. Mutation of alanine\u200553 to glutamate, as found in patients with early\u2010onset PD, weakens the interaction of \u03b1\u2010synuclein with CypA. Our study provides high\u2010resolution insights into the structure of the PD\u2010associated protein \u03b1\u2010synuclein in complex with the most abundant cellular cyclophilin.<\/jats:p>","DOI":"10.1002\/anie.201914878","type":"journal-article","created":{"date-parts":[[2019,12,12]],"date-time":"2019-12-12T14:41:41Z","timestamp":1576161701000},"page":"5643-5646","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["The Molecular Basis of the Interaction of Cyclophilin\u2005A with \u03b1\u2010Synuclein"],"prefix":"10.1002","volume":"59","author":[{"given":"Filippo","family":"Favretto","sequence":"first","affiliation":[{"name":"Translational Structural Biology in Dementia German Center for Neurodegenerative Diseases (DZNE)  Von-Siebold-Str. 3a 37075 G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy 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