Dynamic coupling of residues within proteins as a mechanistic foundation of many enigmatic pathogenic missense variants

Nicholas J. Ose, Brandon M. Butler, Avishek Kumar, I. Can Kazan, Maxwell Sanderford, Sudhir Kumar, S. Banu Ozkan

Research output: Contribution to journalArticlepeer-review

Abstract

Many pathogenic missense mutations are found in protein positions that are neither wellconserved nor fall in any known functional domains. Consequently, we lack any mechanistic underpinning of dysfunction caused by such mutations. We explored the disruption of allosteric dynamic coupling between these positions and the known functional sites as a possible mechanism for pathogenesis. In this study, we present an analysis of 591 pathogenic missense variants in 144 human enzymes that suggests that allosteric dynamic coupling of mutated positions with known active sites is a plausible biophysical mechanism and evidence of their functional importance. We illustrate this mechanism in a case study of β-Glucocerebrosidase (GCase) in which a vast majority of 94 sites harboring Gaucher diseaseassociated missense variants are located some distance away from the active site. An analysis of the conformational dynamics of GCase suggests that mutations on these distal sites cause changes in the flexibility of active site residues despite their distance, indicating a dynamic communication network throughout the protein. The disruption of the long-distance dynamic coupling caused by missense mutations may provide a plausible general mechanistic explanation for biological dysfunction and disease.

Original languageEnglish (US)
Article numbere1010006
JournalPLoS computational biology
Volume18
Issue number4
DOIs
StatePublished - Apr 2022
Externally publishedYes

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Ecology
  • Modeling and Simulation
  • Molecular Biology
  • Genetics
  • Cellular and Molecular Neuroscience
  • Computational Theory and Mathematics

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