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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. Here 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 α -synuclein's C-terminal domain. 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.