Basal oxidation of conserved cysteines modulates cardiac titin stiffness and dynamics
| Autor: | 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 |
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| Přispěvatelé: | Ministerio de Ciencia e Innovación (España), Comunidad de Madrid (España), European Research Council, European Science Foundation, Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Instituto de Salud Carlos III, Fundación La Caixa, European Research Area Network on Cardiovascular Diseases, FWF Austrian Science Fund, Fundación ProCNIC, Agencia Estatal de Investigación (España), Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España), Acciona, Comunidad de Madrid, Austrian Science Fund, Subprograma de Apoyo a Centros de Excelencia Severo Ochoa (MINECO), España |
| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Repisalud Instituto de Salud Carlos III (ISCIII) |
| ISSN: | 2213-2317 |
| DOI: | 10.1016/j.redox.2022.102306 |
| Popis: | 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. This work was supported by the Ministerio de Ciencia e Innovación (MCIN/AEI/10.13039/501100011033) grants BIO2014-54768-P, BIO2017-83640-P (AEI/FEDER, UE), PID2020-120426GB-I00, RYC2014-16604 to JAC and PGC2018-097019-B-I00 to JV, the Regional Government of Madrid grants S2018/NMT-4443 (Tec4Bio, 50% cofinanced by the European Social Fund and the European Regional Development Fund for the programming period 2014-2020) and PEJ16/MED/TL-1593 to JAC and the Instituto de Salud Carlos III (Fondo de Investigacion ´ Sanitaria grant PRB3, PT17/0019/0003- ISCIII-SGEFI /ERDF, ProteoRed), and “la Caixa” Banking Foundation (project code HR17-00247) to JV. We acknowledge funding from the European Research Area Network on Cardiovascular Diseases through grant MINOTAUR to SS (The Austrian Science Fund – FWF, I3301) and JAC (ISCIII-AC16/00045). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovacion ´ (MCIN) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MCIN/AEI/10.13039/501100011033). IMM was the recipient of a CNIC-ACCIONA Masters Fellowship and holds a fellowship from “La Caixa” Foundation (ID 100010434, fellowship code LCF/BQ/DR20/11790009). CSC is the recipient of an FPI-SO predoctoral fellowship BES-2016-076638. We thank Wolfgang A. Linke and Pablo García-Pavía for critical feedback. We are also thankful for the insights of four anonymous reviewers. Sí |
| Databáze: | OpenAIRE |
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