The Molecular Basis of the Interaction of Cyclophilin A with α‐Synuclein
| العنوان: | The Molecular Basis of the Interaction of Cyclophilin A with α‐Synuclein |
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| المؤلفون: | Laura J. Blair, Loren B. Andreas, Jeremy D. Baker, Markus Zweckstetter, Timo Strohäker, Filippo Favretto, Stefan Becker |
| المصدر: | Angewandte Chemie (International Ed. in English) Angewandte Chemie / International edition 59(14), 5643-5646 (2020). doi:10.1002/anie.201914878 |
| بيانات النشر: | Wiley, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | metabolism [Cyclophilin A], Parkinson's disease, animal diseases, Cypa, Isomerase, Crystallography, X-Ray, medicine.disease_cause, 01 natural sciences, chemistry [Cyclophilin A], Protein structure, metabolism [alpha-Synuclein], Cyclophilin, Alanine, Mutation, biology, Chemistry, Communication, General Medicine, Nuclear magnetic resonance spectroscopy, ddc:540, cyclophilin, genetics [alpha-Synuclein], alpha-Synuclein, chemistry [Proline], Cyclophilin A, Protein Binding, Proline, Stereochemistry, Molecular Dynamics Simulation, 010402 general chemistry, Catalysis, α-synuclein, Isomerism, medicine, Amino Acid Sequence, protein structure, Nuclear Magnetic Resonance, Biomolecular, Binding Sites, 010405 organic chemistry, General Chemistry, biology.organism_classification, Communications, nervous system diseases, 0104 chemical sciences, chemistry [alpha-Synuclein], nervous system, Biocatalysis, Mutagenesis, Site-Directed, Protein–Protein Interactions, proline isomerization |
| الوصف: | 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 47GVVHGVATVA56, 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. The high‐resolution structure of the PreNAC region of α‐synuclein in complex with the peptidylprolyl isomerase cyclophilin A provides a novel entry point for the modulation of α‐synuclein‐related neurotoxicity. The A53E mutation of α‐synuclein, which causes early‐onset Parkinson's disease, weakens the interaction of α‐synuclein with cyclophilin A. |
| تدمد: | 1521-3773 1433-7851 |
| DOI: | 10.1002/anie.201914878 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2c6ee590a485fc02c7c723ef615c1d07 https://doi.org/10.1002/anie.201914878 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....2c6ee590a485fc02c7c723ef615c1d07 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15213773 14337851 |
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| DOI: | 10.1002/anie.201914878 |