Structural Basis for Modulation of Quality Control Fate in a Marginally Stable Protein
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Structural basis.pdf
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Author(s)
Abraham, Ayelet-chen
Amen, Triana
Kaganovich, Daniel
Brock, Kelly Paige
England, Jeremy L.
Date Issued
May 2015
Journal
Structure
Publisher
Elsevier
Citation
Brock, Kelly P.; Abraham, Ayelet-chen; Amen, Triana; Kaganovich, Daniel and England, Jeremy L. “Structural Basis for Modulation of Quality Control Fate in a Marginally Stable Protein.” Structure 23, no. 7 (July 2015): 1169–1178.
Version
Final published version
Abstract
The human von Hippel-Lindau (VHL) tumor suppressor is a marginally stable protein previously used as a model substrate of eukaryotic refolding and degradation pathways. When expressed in the absence of its cofactors, VHL cannot fold and is quickly degraded by the quality control machinery of the cell. We combined computational methods with in vivo experiments to examine the basis of the misfolding propensity of VHL. By expressing a set of randomly mutated VHL sequences in yeast, we discovered a more stable mutant form. Subsequent modeling suggested the mutation had caused a conformational change affecting cofactor and chaperone interaction, and this hypothesis was then confirmed by additional knockout and overexpression experiments targeting a yeast cofactor homolog. These findings offer a detailed structural basis for the modulation of quality control fate in a model misfolded protein and highlight burial mode modeling as a rapid means to detect functionally important conformational changes in marginally stable globular domains.
MIT Department
Massachusetts Institute of Technology. Computational and Systems Biology Program
Massachusetts Institute of Technology. Department of Physics
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Creative Commons Attribution 4.0 International License
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DOI of Published Version
https://doi.org/10.1016/j.str.2015.04.015
