Por favor, use este identificador para citar o enlazar este Item:http://hdl.handle.net/20.500.12105/15642
Título
Basal oxidation of conserved cysteines modulates cardiac titin stiffness and dynamics.
Autor(es)
Herrero-Galán, Elías | Martínez-Martín, Inés | Sanchez-Gonzalez, Cristina CNIC | Vicente, Natalia | Bonzón-Kulichenko, Elena | Calvo, Enrique CNIC | Suay-Corredera, Carmen CNIC | Pricolo, Maria Rosaria | Fernández-Trasancos, Ángel | Velázquez-Carreras, Diana | Careaga, Claudio Badía | Abdellatif, Mahmoud | Sedej, Simon | Rainer, Peter P | Giganti, David | Pérez-Jiménez, Raúl | Vazquez, Jesus CNIC | Alegre-Cebollada, Jorge CNIC
Fecha de publicación
2022-06
Cita
Redox Biol. 2022 Jun;52:102306
Idioma
Inglés
Tipo de documento
journal article
Resumen
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.
MESH
Heart Diseases | Sarcomeres | Animals | Connectin | Cysteine | Elasticity | Humans | Mice | Myocardium | Oxidation-Reduction | Protein Kinases
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DOI
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