S-glutathionylation of cryptic cysteines enhances titin elasticity by blocking protein folding

Cell. 2014 Mar 13;156(6):1235-1246. doi: 10.1016/j.cell.2014.01.056.

Abstract

The giant elastic protein titin is a determinant factor in how much blood fills the left ventricle during diastole and thus in the etiology of heart disease. Titin has been identified as a target of S-glutathionylation, an end product of the nitric-oxide-signaling cascade that increases cardiac muscle elasticity. However, it is unknown how S-glutathionylation may regulate the elasticity of titin and cardiac tissue. Here, we show that mechanical unfolding of titin immunoglobulin (Ig) domains exposes buried cysteine residues, which then can be S-glutathionylated. S-glutathionylation of cryptic cysteines greatly decreases the mechanical stability of the parent Ig domain as well as its ability to fold. Both effects favor a more extensible state of titin. Furthermore, we demonstrate that S-glutathionylation of cryptic cysteines in titin mediates mechanochemical modulation of the elasticity of human cardiomyocytes. We propose that posttranslational modification of cryptic residues is a general mechanism to regulate tissue elasticity.

Publication types

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

MeSH terms

  • Biomechanical Phenomena
  • Connectin / chemistry*
  • Connectin / metabolism*
  • Cysteine / metabolism
  • Elasticity
  • Glutaredoxins / metabolism
  • Humans
  • Models, Molecular
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism*
  • Protein Folding
  • Protein Processing, Post-Translational*
  • Protein Structure, Tertiary

Substances

  • Connectin
  • Glutaredoxins
  • TTN protein, human
  • Cysteine