The Molecular Basis of the Interaction of Cyclophilin A with α‐Synuclein

Autor: Laura J. Blair, Loren B. Andreas, Jeremy D. Baker, Markus Zweckstetter, Timo Strohäker, Filippo Favretto, Stefan Becker
Rok vydání: 2020
Předmět:
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
Zdroj: Angewandte Chemie (International Ed. in English)
Angewandte Chemie / International edition 59(14), 5643-5646 (2020). doi:10.1002/anie.201914878
ISSN: 1521-3773
1433-7851
Popis: 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.
Databáze: OpenAIRE
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