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Cell. 2014 Mar 13;156(6):1235-46. doi: 10.1016/j.cell.2014.01.056.

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

Author information

1
Department of Biological Sciences, Columbia University, New York, NY 10027, USA. Electronic address: ja2544@columbia.edu.
2
Department of Biological Sciences, Columbia University, New York, NY 10027, USA; Graduate Program in Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
3
Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
4
Department of Biological Sciences, Columbia University, New York, NY 10027, USA; Columbia College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
5
Department of Cardiovascular Physiology, Ruhr University Bochum, 44780 Bochum, Germany.
6
Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
7
Department of Biological Sciences, Columbia University, New York, NY 10027, USA. Electronic address: jfernandez@columbia.edu.

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.

PMID:
24630725
PMCID:
PMC3989842
DOI:
10.1016/j.cell.2014.01.056
[Indexed for MEDLINE]
Free PMC Article
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