Basal oxidation of conserved cysteines modulates cardiac titin stiffness and dynamics.

Abstract

Titin, as the main protein responsible for the passive stiffness of the sarcomere, plays a key role in diastolic function and is a determinant factor in the etiology of heart disease. Titin stiffness depends on unfolding and folding transitions of immunoglobulin-like (Ig) domains of the I-band, and recent studies have shown that oxidative modifications of cryptic cysteines belonging to these Ig domains modulate their mechanical properties in vitro. However, the relevance of this mode of titin mechanical modulation in vivo remains largely unknown. Here, we describe the high evolutionary conservation of titin mechanical cysteines and show that they are remarkably oxidized in murine cardiac tissue. Mass spectrometry analyses indicate a similar landscape of basal oxidation in murine and human myocardium. Monte Carlo simulations illustrate how disulfides and S-thiolations on these cysteines increase the dynamics of the protein at physiological forces, while enabling load- and isoform-dependent regulation of titin stiffness. Our results demonstrate the role of conserved cysteines in the modulation of titin mechanical properties in vivo and point to potential redox-based pathomechanisms in heart disease.

• Authors: Elías Herrero-Galán, Inés Martínez-Martín, Cristina Sánchez-González, Natalia Vicente, Elena Bonzón-Kulichenko, Enrique Calvo, Carmen Suay-Corredera, Maria Rosaria Pricolo, Ángel Fernández-Trasancos, Diana Velázquez-Carreras, Claudio Badía Careaga, Mahmoud Abdellatif, Simon Sedej, Peter P Rainer, David Giganti, Raúl Pérez-Jiménez, Jesús Vázquez, Jorge Alegre-Cebollada
• Journal: Redox biology (Redox Biol) Vol. 52 Pg. 102306 (06 2022) ISSN: 2213-2317 [Electronic] Netherlands
• PMID: 35367810 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Connectin
• Protein Kinases
• titin protein, mouse
• Cysteine

Topics

• Animals
• Connectin (chemistry)
• Cysteine (metabolism)
• Elasticity
• Heart Diseases (metabolism)
• Humans
• Mice
• Myocardium (metabolism)
• Oxidation-Reduction
• Protein Kinases (genetics, metabolism)
• Sarcomeres (metabolism)