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dc.contributor.authorHerrero-Galan, Elas 
dc.contributor.authorMartinez-Martin, Ines 
dc.contributor.authorSanchez-Gonzalez, Cristina 
dc.contributor.authorVicente, Natalia
dc.contributor.authorBonzon-Kulichenko, Elena 
dc.contributor.authorCalvo, Enrique 
dc.contributor.authorSuay-Corredera, Carmen 
dc.contributor.authorPricolo, Maria Rosaria
dc.contributor.authorFernández-Trasancos, Ángel
dc.contributor.authorVelázquez-Carreras, Diana
dc.contributor.authorBadia-Careaga, Claudio 
dc.contributor.authorAbdellatif, Mahmoud
dc.contributor.authorSedej, Simon
dc.contributor.authorRainer, Peter P.
dc.contributor.authorGiganti, David
dc.contributor.authorPérez-Jiménez, Raúl
dc.contributor.authorVazquez, Jesus 
dc.contributor.authorAlegre-Cebollada, Jorge
dc.identifier.citationRedox Biol. 2022; 102306es_ES
dc.description.abstractTitin, 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.es_ES
dc.description.sponsorshipThis work was supported by the Ministerio de Ciencia e Innovación grants BIO2014-54768-P, BIO2017-83640-P, RYC-2014-16604 to JAC and PGC2018-097019-B-I00 to JV, the Regional Government of Madrid grants S2018/NMT-4443 and PEJ16/MED/TL-1593 to JAC and the Instituto de Salud Carlos III (Fondo de Investigación 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 Disease through grant MINOTAUR to SS (The Austrian Science Fund – FWF, I3301) and JAC (ISCIII-AC16/00045). The CNIC is supported by ISCIII, the Ministerio de Ciencia e Innovación and the Pro CNIC Foundation, and was a Severo Ochoa Center of Excellence (SEV-2015-0505). 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 three anonymous reviewers.es_ES
dc.publisherElsevier es_ES
dc.titleBasal oxidation of conserved cysteines modulates cardiac titin stiffness and dynamicses_ES
dc.typejournal articlees_ES
dc.rights.licenseAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.contributor.funderMinisterio de Ciencia e Innovación (España)es_ES
dc.contributor.funderComunidad de Madrid es_ES
dc.contributor.funderInstituto de Salud Carlos III es_ES
dc.contributor.funderFundación La Caixaes_ES
dc.contributor.funderAustrian Science Fundes_ES
dc.contributor.funderFundación ProCNICes_ES
dc.contributor.funderSubprograma de Apoyo a Centros de Excelencia Severo Ochoa (MINECO), Españaes_ES
dc.identifier.journalRedox Biologyes_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Mecánica molecular del sistema cardiovasculares_ES
dc.rights.accessRightsopen accesses_ES
dc.relation.projectFISinfo:eu-repo/grantAgreement/ES/PT17/0019/0003- ISCIII-SGEFI /ERDFes_ES

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Attribution-NonCommercial-NoDerivatives 4.0 Internacional
This item is licensed under a: Attribution-NonCommercial-NoDerivatives 4.0 Internacional