Catalysis of proline isomerization and molecular chaperone activity in a tug-of-war

Filippo Favretto, David Flores, Jeremy D. Baker, Timo Strohäker, Loren B. Andreas, Laura J. Blair, Stefan Becker and Markus Zweckstetter ()
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Filippo Favretto: German Center for Neurodegenerative Diseases (DZNE)
David Flores: German Center for Neurodegenerative Diseases (DZNE)
Jeremy D. Baker: Morsani College of Medicine, USF Health Byrd Alzheimer’s Institute, University of South Florida
Timo Strohäker: German Center for Neurodegenerative Diseases (DZNE)
Loren B. Andreas: Max Planck Institute for Biophysical Chemistry
Laura J. Blair: Morsani College of Medicine, USF Health Byrd Alzheimer’s Institute, University of South Florida
Stefan Becker: Max Planck Institute for Biophysical Chemistry
Markus Zweckstetter: German Center for Neurodegenerative Diseases (DZNE)

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract Catalysis of cis/trans isomerization of prolines is important for the activity and misfolding of intrinsically disordered proteins. Catalysis is achieved by peptidylprolyl isomerases, a superfamily of molecular chaperones. Here, we provide atomic insight into a tug-of-war between cis/trans isomerization and molecular chaperone activity. Catalysis of proline isomerization by cyclophilin A lowers the energy barrier for α-synuclein misfolding, while isomerase-binding to a separate, disease-associated protein region opposes aggregation. We further show that cis/trans isomerization outpowers the holding activity of cyclophilin A. Removal of the proline isomerization barrier through posttranslational truncation of α-synuclein reverses the action of the proline isomerase and turns it into a potent molecular chaperone that inhibits protein misfolding. The data reveal a conserved mechanism of dual functionality in cis/trans isomerases and define its molecular determinants acting on intrinsically disordered proteins.

Date: 2020
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DOI: 10.1038/s41467-020-19844-0

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