Structure of prion β-oligomers as determined by short-distance crosslinking constraint-guided discrete molecular dynamics simulations
| dc.contributor.author | Serpa, Jason J. | |
| dc.contributor.author | Popov, Konstantin I. | |
| dc.contributor.author | Petrotchenk, Evgeniy V. | |
| dc.contributor.author | Dokholyan, Nikolay V. | |
| dc.contributor.author | Borchers, Christoph H. | |
| dc.date.accessioned | 2022-04-01T17:14:50Z | |
| dc.date.available | 2022-04-01T17:14:50Z | |
| dc.date.copyright | 2021 | en_US |
| dc.date.issued | 2021-11 | |
| dc.description.abstract | The conversion of the native monomeric cellular prion protein (PrPC) into an aggregated pathological β-oligomeric form (PrPβ) and an infectious form (PrPSc) is the central element in the development of prion diseases. The structure of the aggregates and the molecular mechanisms of the conformational changes involved in the conversion are still unknown. We applied mass spectrometry combined with chemical crosslinking, hydrogen/deuterium exchange, limited proteolysis, and surface modification for the differential characterization of the native and the urea+acid-converted prion β-oligomer structures to obtain insights into the mechanisms of conversion and aggregation. For the determination of the structure of the monomer and the dimer unit of the β-oligomer, we applied a recently-developed approach for de novo protein structure determination which is based on the incorporation of zero-length and short-distance crosslinking data as intra- and inter-protein constraints in discrete molecular dynamics simulations (CL-DMD). Based on all of the structural-proteomics experimental data and the computationally predicted structures of the monomer units, we propose the potential mode of assembly of the β-oligomer. The proposed β-oligomer assembly provides a clue on the β-sheet nucleation site, and how template-based conversion of the native prion molecule occurs, growth of the prion aggregates, and maturation into fibrils may occur. | en_US |
| dc.description.reviewstatus | Reviewed | en_US |
| dc.description.scholarlevel | Faculty | en_US |
| dc.description.sponsorship | Passan Foundation Natural Sciences and Engineering Research Council of Canada National Institutes of Health. Grant Number: 1R35 GM134864 Genome British Columbia. Grant Number: 264PRO Warren Y. Soper Charitable Trust Terry Fox Research Institute Genome Canada. Grant Number: 264PRO PrioNet Canada Ministry of Science and Higher Education of the Russian Federation. Grant Number: 075-10-2019-083 Alvin Segal Family Foundation | en_US |
| dc.identifier.citation | Serpa, J. J., Popov, K. I., Petrotchenko, E. V., Dokholyan, N. V., & Borchers, C. H. (2021). Structure of prion β-oligomers as determined by short-distance crosslinking constraint-guided discrete molecular dynamics simulations. Proteomics, 21(21-22), https://doi.org/10.1002/pmic.202000298 | en_US |
| dc.identifier.uri | https://doi.org/10.1002/pmic.202000298 | |
| dc.identifier.uri | http://hdl.handle.net/1828/13842 | |
| dc.language.iso | en | en_US |
| dc.publisher | Journal of Proteomics | en_US |
| dc.subject | molecular modeling | |
| dc.subject | protein aggregation | |
| dc.subject | protein folding | |
| dc.subject | structural proteomics | |
| dc.subject | UVic Genome BC Proteomics Centre | |
| dc.subject.department | Department of Biochemistry and Microbiology | |
| dc.title | Structure of prion β-oligomers as determined by short-distance crosslinking constraint-guided discrete molecular dynamics simulations | en_US |
| dc.type | Article | en_US |