title: S-glutathionylation of cryptic cysteines enhances titin elasticity by blocking protein folding.
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.
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA. Electronic address: ja2544@columbia.edu.
authors.forename: Jorge
authors.initials: J
authors.lastname: Alegre-Cebollada
authors.affiliation: 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.
authors.forename: Pallav
authors.initials: P
authors.lastname: Kosuri
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: David
authors.initials: D
authors.lastname: Giganti
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA; Columbia College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Eckels
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Jaime Andrés
authors.initials: JA
authors.lastname: Rivas-Pardo
authors.affiliation: Department of Cardiovascular Physiology, Ruhr University Bochum, 44780 Bochum, Germany.
authors.forename: Nazha
authors.initials: N
authors.lastname: Hamdani
authors.affiliation: Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Chad M
authors.initials: CM
authors.lastname: Warren
authors.affiliation: Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: R John
authors.initials: RJ
authors.lastname: Solaro
authors.affiliation: Department of Cardiovascular Physiology, Ruhr University Bochum, 44780 Bochum, Germany.
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Linke
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA. Electronic address: jfernandez@columbia.edu.
authors.forename: Julio M
authors.initials: JM
authors.lastname: Fernández
mesh_terms: D001696:Biomechanical Phenomena; D064211:Connectin / Q000737:chemistry* / Q000378:metabolism*; D003545:Cysteine / Q000378:metabolism; D004548:Elasticity; D054477:Glutaredoxins / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary
chemical_list: D064211:Connectin; D054477:Glutaredoxins; C577285:TTN protein, human; D003545:Cysteine