Journal
STRUCTURE
Volume 27, Issue 11, Pages 1710-+Publisher
CELL PRESS
DOI: 10.1016/j.str.2019.09.003
Keywords
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Funding
- Genome Canada through the Genomics Innovation Network [204PRO, 214PRO]
- Genome Canada through Genomics Technology Platform [264PRO]
- Genome British Columbia through the Genomics Innovation Network [204PRO, 214PRO]
- Genome British Columbia through Genomics Technology Platform [264PRO]
- Natural Sciences and Engineering Research Council of Canada of Canada (NSERC)
- Leading Edge Endowment Fund
- Segal McGill Chair in Molecular Oncology at McGill University (Montreal, QC, Canada)
- Warren Y. Soper Charitable Trust
- Alvin Segal Family Foundation
- NIH [R01GM080742, R01GM114015, R01GM123247]
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Combining structural proteomics experimental data with computational methods is a powerful tool for protein structure prediction. Here, we apply a recently developed approach for de novo protein structure determination based on the incorporation of short-distance crosslinking data as constraints in discrete molecular dynamics simulations (CL-DMD), for the determination of the conformational ensemble of tau protein in solution. The predicted structures were in agreement with surface modification and long-distance crosslinking data. Tau in solution was found as an ensemble of rather compact globular conformations with distinct topology, inter-residue contacts, and a number of transient secondary-structure elements. Regions important for pathological aggregation consistently were found to contain b strands. The determined structures are compatible with the tau protein in solution being a molten globule at near-ground state with persistent residual structural features which we were able to capture by CL-DMD. The predicted structure may facilitate an understanding of the misfolding and oligomerization pathways of the tau protein.
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