The Molecular Basis of the Interaction of Cyclophilin A with α-Synuclein

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.