Structural Capacitance in Protein Evolution and Human Diseases

Chen Li, Liahona V.T. Clark, Rory Zhang, Benjamin T. Porebski, Julia M. McCoey, Natalie A. Borg, Geoffrey I. Webb, Itamar Kass, Malcolm Buckle, Jiangning Song, Adrian Woolfson, Ashley M. Buckle

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)

Abstract

Canonical mechanisms of protein evolution include the duplication and diversification of pre-existing folds through genetic alterations that include point mutations, insertions, deletions, and copy number amplifications, as well as post-translational modifications that modify processes such as folding efficiency and cellular localization. Following a survey of the human mutation database, we have identified an additional mechanism that we term “structural capacitance,” which results in the de novo generation of microstructure in previously disordered regions. We suggest that the potential for structural capacitance confers select proteins with the capacity to evolve over rapid timescales, facilitating saltatory evolution as opposed to gradualistic canonical Darwinian mechanisms. Our results implicate the elements of protein microstructure generated by this distinct mechanism in the pathogenesis of a wide variety of human diseases. The benefits of rapidly furnishing the potential for evolutionary change conferred by structural capacitance are consequently counterbalanced by this accompanying risk. The phenomenon of structural capacitance has implications ranging from the ancestral diversification of protein folds to the engineering of synthetic proteins with enhanced evolvability.

Original languageEnglish
Pages (from-to)3200-3217
Number of pages18
JournalJournal of Molecular Biology
Volume430
Issue number18
DOIs
Publication statusPublished - 14 Sep 2018

Keywords

  • disorder–order transition
  • human diseases
  • protein disordered region
  • protein evolution
  • structural capacitance

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