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

Favretto, F., Flores, D., Baker, J. D., Strohäker, T., Andreas, L. B., Blair, L. J., et al. (2020). Catalysis of proline isomerization and molecular chaperone activity in a tug-of-war. Nature Communications, 11: 6046. doi:10.1038/s41467-020-19844-0.

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Favretto, F., Author
Flores, D., Author
Baker, J. D., Author
Strohäker, T.1, Author              
Andreas, L. B.2, Author              
Blair, L. J., Author
Becker, S.3, Author              
Zweckstetter, M.4, 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              
4Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              

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Free keywords: Biochemistry; Intrinsically disordered proteins; Solution-state NMR
 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.

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Language(s): eng - English
 Dates: 2020-11-27
 Publication Status: Published online
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 Rev. Type: Peer
 Identifiers: DOI: 10.1038/s41467-020-19844-0
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Title: Nature Communications
Source Genre: Journal
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Pages: 12 Volume / Issue: 11 Sequence Number: 6046 Start / End Page: - Identifier: -