S-Glutathionylation of Cryptic Cysteines Enhances Titin Elasticity by Blocking Protein Folding

Fernandez, Julio M.; Hamdani, Nazha; Alegre-Cebollada, Jorge; Warren, Chad M.; Giganti, David; Solaro, R. John; Rivas-Pardo, Jaime Andres; Linke, Wolfgang A.; Eckels, Edward; Kosuri, Pallav


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 post-translational modification of cryptic residues is a general mechanism to regulate tissue elasticity.

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Título según WOS: ID WOS:000332945100013 Not found in local WOS DB
Título de la Revista: CELL
Volumen: 156
Número: 6
Editorial: Cell Press
Fecha de publicación: 2014
Página de inicio: 1235
Página final: 1246


Notas: ISI