6I42

Structure of the alpha-Synuclein PreNAC/Cyclophilin A-complex

Summary for 6I42

• Entry DOI: 10.2210/pdb6i42/pdb
• Descriptor: Peptidyl-prolyl cis-trans isomerase A, Alpha-synuclein (3 entities in total)
• Functional Keywords: cyclophilin a, peptidyl-prolyl isomerase, alpha-synuclein, prenac, isomerase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 19246.88

Authors

Favretto, F.,Zweckstetter, M.,Becker, S. (deposition date: 2018-11-08, release date: 2020-02-19, Last modification date: 2024-01-24)

Primary citation

Favretto, F.,Baker, J.D.,Strohaker, T.,Andreas, L.B.,Blair, L.J.,Becker, S.,Zweckstetter, M.
The Molecular Basis of the Interaction of Cyclophilin A with alpha-Synuclein.
Angew.Chem.Int.Ed.Engl., 59:5643-5646, 2020

PubMed 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 GVVHGVATVA , 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.

PubMed: 31830361
DOI: 10.1002/anie.201914878

Experimental method

X-RAY DIFFRACTION (1.38 Å)