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

Favretto, F., Baker, J., Strohäker, T., Andreas, L., Blair, L., Becker, S., et al. (2019). Molecular basis of the interaction of cyclophilin A with alpha-synuclein. Angewandte Chemie International Edition, (in press). doi:10.1002/anie.201914878.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0005-5C74-2 Version Permalink: http://hdl.handle.net/21.11116/0000-0005-5C77-F
Genre: Journal Article

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3182304_Suppl.htm (Supplementary material), 6MB
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 Creators:
Favretto, F., Author
Baker, J., Author
Strohäker, T.1, Author              
Andreas, L.2, Author              
Blair, L., Author
Becker, S.3, Author              
Zweckstetter, M.1, Author              
Affiliations:
1Research Group of Protein Structure Determination using NMR, MPI for Biophysical Chemistry, Max Planck Society, ou_578571              
2Research Group of Solid State NMR Spectroscopy-2, MPI for Biophysical Chemistry, Max Planck Society, ou_2396693              
3Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              

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Free keywords: Parkinson's disease; cyclophilin; proline isomerization; structure; α-synuclein
 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.

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Language(s): eng - English
 Dates: 2019-12-12
 Publication Status: Published online
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 Rev. Method: Peer
 Identifiers: DOI: 10.1002/anie.201914878
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Title: Angewandte Chemie International Edition
Source Genre: Journal
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