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Journal Article

Molecular basis of the interaction of cyclophilin A with alpha-synuclein.

MPS-Authors
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Strohäker,  T.
Research Group of Protein Structure Determination using NMR, MPI for Biophysical Chemistry, Max Planck Society;

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Andreas,  L.
Research Group of Solid State NMR Spectroscopy-2, MPI for Biophysical Chemistry, Max Planck Society;

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Becker,  S.
Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society;

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Zweckstetter,  M.
Research Group of Protein Structure Determination using NMR, MPI for Biophysical Chemistry, Max Planck Society;

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Fulltext (public)

3182304.pdf
(Publisher version), 2MB

Supplementary Material (public)

3182304-Suppl.pdf
(Supplementary material), 553KB

Citation

Favretto, F., Baker, J., Strohäker, T., Andreas, L., Blair, L., Becker, S., et al. (2020). Molecular basis of the interaction of cyclophilin A with alpha-synuclein. Angewandte Chemie International Edition, 132(14), 5692-5695. doi:10.1002/anie.201914878.


Cite as: http://hdl.handle.net/21.11116/0000-0005-5C74-2
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.