The Dark Side of Actin: Cardiac actin variants highlight the role of allostery in disease development

Arch Biochem Biophys. 2020 Nov 30:695:108624. doi: 10.1016/j.abb.2020.108624. Epub 2020 Oct 10.

Abstract

Mutations in the α-cardiac actin ACTC1 gene cause dilated or hypertrophic cardiomyopathy. These diseases are the result of changes in protein interactions between ACTC protein and force-generating β-myosin or the calcium-dependent cardiac-tropomyosin (cTm) and cardiac troponin (cTn) regulatory complex, altering the overall contractile force. The T126I and S271F ACTC variants possess amino acid substitutions on the other side of actin relative to the myosin or regulatory protein binding sites on what we call the "dark side" of actin. The T126I change results in hyposensitivity to calcium, in accordance with the calcium sensitivity pathway of cardiomyopathy development while the S271F change alters the maximum in vitro motility sliding speed, reflecting a change in maximum force. These results demonstrate the role of actin allostery in the cardiac disease development.

Keywords: Actin; Allostery; Altered force pathway; Calcium sensitivity pathway; Cardiomyopathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / chemistry*
  • Actins / genetics
  • Actins / metabolism
  • Allosteric Regulation
  • Amino Acid Substitution
  • Animals
  • Cardiomyopathies*
  • Humans
  • Mutation, Missense
  • Sf9 Cells
  • Spodoptera
  • Troponin / chemistry
  • Troponin / genetics
  • Troponin / metabolism

Substances

  • ACTC1 protein, human
  • Actins
  • Troponin