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Titin domains with reduced core hydrophobicity cause dilated cardiomyopathy

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dc.contributor.author Martínez-Martín, Inés
dc.contributor.author Crousilles, Audrey
dc.contributor.author Ochoa, Juan Pablo
dc.contributor.author Velázquez-Carreras, Diana
dc.contributor.author Mortensen, Simon A.
dc.contributor.author Herrero-Galán, Elías
dc.contributor.author Delgado Blanco, Javier
dc.contributor.author Domínguez, Fernando
dc.contributor.author García-Pavía, Pablo
dc.contributor.author Sancho, David de
dc.contributor.author Wilmanns, Matthias
dc.contributor.author Alegre-Cebollada, Jorge
dc.date.accessioned 2024-02-13T07:19:01Z
dc.date.available 2024-02-13T07:19:01Z
dc.date.issued 2023
dc.identifier.citation Martinez-Martin I, Crousilles A, Ochoa JP, Velazquez-Carreras D, Mortensen SA, Herrero-Galan E, Delgado J, Dominguez F, Garcia-Pavia P, de Sancho D, Wilmanns M, Alegre-Cebollada J. Titin domains with reduced core hydrophobicity cause dilated cardiomyopathy. Cell Rep. 2023 Dec 26;42(12):113490. DOI: 10.1016/j.celrep.2023.113490
dc.identifier.issn 2211-1247
dc.identifier.uri http://hdl.handle.net/10230/59088
dc.description.abstract The underlying genetic defect in most cases of dilated cardiomyopathy (DCM), a common inherited heart disease, remains unknown. Intriguingly, many patients carry single missense variants of uncertain pathogenicity targeting the giant protein titin, a fundamental sarcomere component. To explore the deleterious potential of these variants, we first solved the wild-type and mutant crystal structures of I21, the titin domain targeted by pathogenic variant p.C3575S. Although both structures are remarkably similar, the reduced hydrophobicity of deeply buried position 3575 strongly destabilizes the mutant domain, a scenario supported by molecular dynamics simulations and by biochemical assays that show no disulfide involving C3575. Prompted by these observations, we have found that thousands of similar hydrophobicity-reducing variants associate specifically with DCM. Hence, our results imply that titin domain destabilization causes DCM, a conceptual framework that not only informs pathogenicity assessment of gene variants but also points to therapeutic strategies counterbalancing protein destabilization.
dc.description.sponsorship J.A.-C. acknowledges funding from the Ministerio de Ciencia e Innovación (MCIN, MCIN/AEI/10.13039/501100011033) through grants BIO2017-83640-P (AEI/FEDER, EU), PID2020-120426GB-I00, and RED2022-134242-T and the Regional Government of Madrid (grant Tec4Bio S2018/NMT-4443, 50% co-financed by the European Social Fund and the European Regional Development Fund for the programming period 2014–2020). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the MCIN, and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MCIN). I.M.-M. holds a fellowship from 'la Caixa' Foundation (ID 100010434, fellowship code LCF/BQ/DR20/11790009) and received support from a Erasmus + Training fellowship. Financial support to D.d.S. comes from Eusko Jaurlaritza (Basque Government) through the project IT1584-22 and from the MCIN through grants PID2021-127907NB-I00 (AEI/FEDER, UE) and RYC-2016-19590 (AEI/FSE, EU). We thank Maria Rosaria Pricolo for analysis support with database analysis, Vytautas Gapsys for his assistance using the pmx software package, and the staff at the DIPC Supercomputing Center and the Sample Preparation and Characterization facility of the EMBL Hamburg Unit for technical support. The synchrotron data were collected at beamline operated by EMBL Hamburg at the PETRA III storage ring (DESY, Hamburg, Germany). We thank the Spectroscopy and Nuclear Magnetic Resonance Core Unit at CNIO for access to CD instrumentation. Biorender.com was used as a source for icons included in some of the figures of this paper.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Elsevier
dc.relation.ispartof Cell Rep. 2023 Dec 26;42(12):113490
dc.rights © 2023 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.title Titin domains with reduced core hydrophobicity cause dilated cardiomyopathy
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1016/j.celrep.2023.113490
dc.subject.keyword CP: Genomics
dc.subject.keyword CP: Molecular biology
dc.subject.keyword Titin
dc.subject.keyword Missense variants
dc.subject.keyword Dilated cardiomyopathy
dc.subject.keyword Hydrophobicity
dc.subject.keyword Protein stability
dc.subject.keyword Mutation
dc.subject.keyword Protein structure
dc.subject.keyword Molecular dynamics
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BIO2017-83640-P
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-120426GB-I00
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/RED2022-134242-T
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/CEX2020-001041-S
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-127907NB-I00
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/RYC-2016-19590
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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