Ligand-induced disorder-to-order transitions characterized by structural proteomics and molecular dynamics simulations

dc.contributor.authorMakepeace, Karl A.T.
dc.contributor.authorBrodie, Nicolas I.
dc.contributor.authorPopov, Konstantin I.
dc.contributor.authorGudavicius, Geoff
dc.contributor.authorNelson, Christoph J.
dc.contributor.authorPetrochenko, Evgeniy V.
dc.contributor.authorDokholyan, Nikolay V.
dc.contributor.authorBorchers, Christoph H.
dc.date.accessioned2020-03-09T17:11:23Z
dc.date.available2020-03-09T17:11:23Z
dc.date.copyright2020en_US
dc.date.issued2020
dc.description.abstractFor disordered proteins, ligand binding can be a critical event that changes their structural dynamics. The ability to characterize such changes would facilitate the development of drugs designed to stabilize disordered proteins, whose mis-folding is important for a number of pathologies, including neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. In this study, we used hydrogen/deuterium exchange, differential crosslinking, differential surface modification, and molecular dynamics (MD) simulations to characterize the structural changes in disordered proteins that result from ligand binding. We show here that both an ATP-independent protein chaperone, Spy L32P, and the FK506 binding domain of a prolyl isomerase, FKBP-25 F145A/I223P, are disordered, yet exhibit structures that are distinct from chemically denatured unfolded states in solution, and that they undergo transitions to a more structured state upon ligand binding. These systems may serve as models for the characterization of ligand-induced disorder-to-order transitions in proteins using structural proteomics approaches.en_US
dc.description.reviewstatusRevieweden_US
dc.description.scholarlevelFacultyen_US
dc.description.sponsorshipThe University of Victoria-Genome British Columbia Proteomics Centre is grateful to Genome Canada and Genome British Columbia for financial support through the (project Genomics Innovation Network (codes 204PRO for operations and 214PRO for technology development) and the Genomics Technology Platform (264PRO). CHB is also grateful for support from the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Leading Edge Endowment Fund (University of Victoria), and for support from the Segal McGill Chair in Molecular Oncology at McGill University (Montreal, Quebec, Canada). CHB is also grateful for support from the Warren Y. Soper Charitable Trust and the Alvin Segal Family Foundation to the Jewish General Hospital (Montreal, Quebec, Canada). NVD also acknowledges support from NIH grants R01GM114015 and R01GM123247.en_US
dc.identifier.citationMakepeace, K.A.T., Brodie, N.I., Popov, K.I., Gudavicius, G., Nelson, C.J., Petrochenko, E.V., Dokholyan, N.V. & Borchers, C.H. (2020). Ligand-induced disorder-to order transitions characterized by structural proteomics and molecular dynamics simulations. Journal of Proteomics, 211, 103544. https://doi.org/10.1016/j.jprot.2019.103544en_US
dc.identifier.urihttps://doi.org/10.1016/j.jprot.2019.103544
dc.identifier.urihttp://hdl.handle.net/1828/11613
dc.language.isoenen_US
dc.publisherJournal of Proteomicsen_US
dc.subjectStructural proteomicsen_US
dc.subjectMass spectrometryen_US
dc.subjectMolecular dynamics simulationsen_US
dc.subjectProtein-ligand interactionen_US
dc.subjectHydrogen/deuterium exchangeen_US
dc.subjectCrosslinking/mass spectrometryen_US
dc.subjectSurface modificationen_US
dc.subjectConformational changeen_US
dc.subjectIntrinsically disordered proteinen_US
dc.subjectProtein foldingen_US
dc.titleLigand-induced disorder-to-order transitions characterized by structural proteomics and molecular dynamics simulationsen_US
dc.typeArticleen_US

Files

Original bundle
Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
Gudavicius_Geoff_JProteomics_2020.pdf
Size:
2.31 MB
Format:
Adobe Portable Document Format
Description:
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
1.71 KB
Format:
Item-specific license agreed upon to submission
Description: