{"doi":"10.1002/ange.201914878","title":"The Molecular Basis of the Interaction of Cyclophilin A with α‐Synuclein","abstract":"<jats:title>Abstract</jats:title><jats:p>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 <jats:sup>47</jats:sup>GVVHGVATVA<jats:sup>56</jats:sup>, 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.</jats:p>","journal":"Angewandte Chemie","year":2020,"id":617632,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":472182,"name":"Jeremy D. Baker","orcid":null,"position":1,"is_corresponding":false},{"id":472183,"name":"Timo Strohäker","orcid":null,"position":2,"is_corresponding":false},{"id":471013,"name":"Loren B. Andreas","orcid":"0000-0003-3216-9065","position":3,"is_corresponding":false},{"id":458570,"name":"Laura J. Blair","orcid":"0000-0002-4981-5564","position":4,"is_corresponding":false},{"id":471014,"name":"Stefan Becker","orcid":"0000-0003-2041-5740","position":5,"is_corresponding":false},{"id":471015,"name":"Markus Zweckstetter","orcid":"0000-0002-2536-6581","position":6,"is_corresponding":false},{"id":471011,"name":"Filippo Favretto","orcid":"0000-0002-2964-1157","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"The Molecular Basis of the Interaction of Cyclophilin A with α‐Synuclein","abstract":"<jats:title>Abstract</jats:title><jats:p>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 <jats:sup>47</jats:sup>GVVHGVATVA<jats:sup>56</jats:sup>, 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.</jats:p>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"19767382","pmcid":null,"openalex_id":"https://openalex.org/W4235663080","authors":[],"funders":[{"funder_name":"Deutsche Forschungsgemeinschaft","grant_id":"AN 1316/1-1","title":null},{"funder_name":"Deutsche Forschungsgemeinschaft","grant_id":"SFB860 (B2)","title":null},{"funder_name":"Foundation for the National Institutes of Health","grant_id":"R01 NS073899","title":null},{"funder_name":"Deutsche Forschungsgemeinschaft","grant_id":"unidentified","title":"unidentified"},{"funder_name":"National Institutes of Health","grant_id":"2R01NS073899-11","title":"The hsp90 Cochaperone FKBP51 Regulates tau Structure and Function"}],"total_grants":5,"fwci":0.0,"citation_percentile":0.18365726,"influential_citations":0,"citation_trend":[],"oa_status":"hybrid","license":"cc-by","oa_locations":[{"url":"https://doi.org/10.1002/ange.201914878","host_type":"journal"},{"url":"https://doi.org/10.1002/ange.201914878","host_type":"publisher"},{"url":"https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1002%2Fange.201914878","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/pdf/10.1002/ange.201914878","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/full-xml/10.1002/ange.201914878","host_type":"publisher"},{"url":"https://doi.org/10.1002/anie.201914878","host_type":""},{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/anie.201914878","host_type":""},{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/ange.201914878","host_type":""},{"url":"https://pubmed.ncbi.nlm.nih.gov/31830361","host_type":""},{"url":"http://dx.doi.org/10.1002/anie.201914878","host_type":""},{"url":"https://dx.doi.org/10.1002/anie.201914878","host_type":""},{"url":"https://pub.dzne.de/record/145033","host_type":""},{"url":"https://hdl.handle.net/11562/1034623","host_type":""}],"fields_of_study":["Signaling Pathways in Disease","Toxin Mechanisms and Immunotoxins","Peptidase Inhibition and Analysis","0301 basic medicine","03 medical and health sciences","0303 health sciences"],"mesh_terms":[],"keywords":["Cypa","Cyclophilin A","Peptidylprolyl isomerase","Cyclophilin","Isomerase","Cis-trans-Isomerases","Chemistry","Alanine","FKBP","Stereochemistry","Biophysics","Crystallography","Biochemistry","Amino acid","Biology","Enzyme","Molecular biology","alpha-Synuclein: chemistry","Cyclophilin A: metabolism","Proline: chemistry","info:eu-repo/classification/ddc/540","alpha-Synuclein: metabolism","Proline","alpha-Synuclein: genetics","Parkinson's disease","Molecular Dynamics Simulation","Crystallography, X-Ray","α-synuclein","Isomerism","Amino Acid Sequence","protein structure","Nuclear Magnetic Resonance, Biomolecular","Cyclophilin A: chemistry","Binding Sites","Communications","Biocatalysis","Mutagenesis, Site-Directed","alpha-Synuclein","proline isomerization","Protein Binding"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-03T02:14:56.772442Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}