Basal oxidation of conserved cysteines modulates cardiac titin stiffness and dynamics
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
Affiliations
Elías Herrero-Galán
Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; Corresponding author.
Inés Martínez-Martín
Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
Cristina Sánchez-González
Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
Natalia Vicente
Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
Elena Bonzón-Kulichenko
Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
Enrique Calvo
Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
Carmen Suay-Corredera
Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
Maria Rosaria Pricolo
Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
Ángel Fernández-Trasancos
Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
Diana Velázquez-Carreras
Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
Claudio Badía Careaga
Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
Mahmoud Abdellatif
Division of Cardiology, Medical University of Graz, Graz, Austria
Simon Sedej
Division of Cardiology, Medical University of Graz, Graz, Austria; Faculty of Medicine, University of Maribor, Maribor, Slovenia; BioTechMed Graz, Graz, Austria
Peter P. Rainer
Division of Cardiology, Medical University of Graz, Graz, Austria; BioTechMed Graz, Graz, Austria
David Giganti
Department of Biochemistry & Molecular Pharmacology and Institute for Systems Genetics, NYU Langone Health, New York, NY, United States
Raúl Pérez-Jiménez
CIC NanoGUNE BRTA, San Sebastian, Spain; Ikerbasque Foundation for Science, Bilbao, Spain
Jesús Vázquez
Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
Jorge Alegre-Cebollada
Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; Corresponding author.
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.