Functional plasticity and evolutionary adaptation of allosteric regulation

Proc Natl Acad Sci U S A. 2020 Oct 13;117(41):25445-25454. doi: 10.1073/pnas.2002613117. Epub 2020 Sep 30.


Allostery is a fundamental regulatory mechanism of protein function. Despite notable advances, understanding the molecular determinants of allostery remains an elusive goal. Our current knowledge of allostery is principally shaped by a structure-centric view, which makes it difficult to understand the decentralized character of allostery. We present a function-centric approach using deep mutational scanning to elucidate the molecular basis and underlying functional landscape of allostery. We show that allosteric signaling exhibits a high degree of functional plasticity and redundancy through myriad mutational pathways. Residues critical for allosteric signaling are surprisingly poorly conserved while those required for structural integrity are highly conserved, suggesting evolutionary pressure to preserve fold over function. Our results suggest multiple solutions to the thermodynamic conditions of cooperativity, in contrast to the common view of a finely tuned allosteric residue network maintained under selection.

Keywords: allostery; deep mutational scanning; functional plasticity; molecular dynamics simulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological*
  • Allosteric Regulation / genetics*
  • Bacteria / cytology*
  • Bacterial Physiological Phenomena*
  • Biological Evolution*
  • Cloning, Molecular
  • Epigenesis, Genetic
  • Flow Cytometry
  • Gene Expression Regulation, Enzymologic
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Mutation
  • Protein Conformation