dc.contributor.author | Suay-Corredera, Carmen | |
dc.contributor.author | Pricolo, Maria Rosaria | |
dc.contributor.author | Velázquez-Carreras, Diana | |
dc.contributor.author | Pathak, Divya | |
dc.contributor.author | Nandwani, Neha | |
dc.contributor.author | Pimenta-Lopes, Carolina | |
dc.contributor.author | Sánchez-Ortiz, David | |
dc.contributor.author | Urrutia-Irazabal, Iñigo | |
dc.contributor.author | Vilches, Silvia | |
dc.contributor.author | Dominguez, Fernando | |
dc.contributor.author | Frisso, Giulia | |
dc.contributor.author | Monserrat, Lorenzo | |
dc.contributor.author | García-Pavía, Pablo | |
dc.contributor.author | de Sancho, David | |
dc.contributor.author | Spudich, James A | |
dc.contributor.author | Ruppel, Kathleen M | |
dc.contributor.author | Herrero-Galán, Elías | |
dc.contributor.author | Alegre-Cebollada, Jorge | |
dc.date.accessioned | 2022-11-16T13:43:01Z | |
dc.date.available | 2022-11-16T13:43:01Z | |
dc.date.issued | 2021 | |
dc.identifier.citation | ACS Nano . 2021 Jun 22;15(6):10203-10216. | es_ES |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/15168 | |
dc.description.abstract | Hypertrophic cardiomyopathy (HCM) is a disease of the myocardium caused by mutations in sarcomeric proteins with mechanical roles, such as the molecular motor myosin. Around half of the HCM-causing genetic variants target contraction modulator cardiac myosin-binding protein C (cMyBP-C), although the underlying pathogenic mechanisms remain unclear since many of these mutations cause no alterations in protein structure and stability. As an alternative pathomechanism, here we have examined whether pathogenic mutations perturb the nanomechanics of cMyBP-C, which would compromise its modulatory mechanical tethers across sliding actomyosin filaments. Using single-molecule atomic force spectroscopy, we have quantified mechanical folding and unfolding transitions in cMyBP-C domains targeted by HCM mutations that do not induce RNA splicing alterations or protein thermodynamic destabilization. Our results show that domains containing mutation R495W are mechanically weaker than wild-type at forces below 40 pN and that R502Q mutant domains fold faster than wild-type. None of these alterations are found in control, nonpathogenic variants, suggesting that nanomechanical phenotypes induced by pathogenic cMyBP-C mutations contribute to HCM development. We propose that mutation-induced nanomechanical alterations may be common in mechanical proteins involved in human pathologies. | es_ES |
dc.description.sponsorship | J.A.C. acknowledges funding from the Ministerio de Ciencia e Innovación (MCIN) through grants BIO2014–
54768-P, BIO2017–83640-P (AEI/FEDER, UE), EIN2019–102966, RYC-2014–16604, and BFU2017–90692
REDT, the European Research Area Network on Cardiovascular Diseases (ERA-CVD/ISCIII, MINOTAUR,
AC16/00045), and the Comunidad de Madrid (consortium Tec4Bio-CM, S2018/NMT-4443, FEDER). This work
was supported by NIH grants RM1 GM33289 and HL117138 to J.A.S.; a Stanford Dean’s Postdoctoral Fellowship
to D.P. and N.N.; and a Stanford Maternal and Child Health Research Institute (MCHRI) Postdoctoral Fellowship
(1220552–140-DHPEU) to N.N. Financial support to D.D.S. comes from Eusko Jaurlaritza (Basque Government)
through the project IT1254–19, and grants RYC-2016–19590 and PGC2018–099321-B-I00 from the MCIN
(FEDER). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), MCIN, and the Pro CNIC
Foundation and was a Severo Ochoa Center of Excellence (SEV-2015–0505). We acknowledge funding from
ISCIII to the Centro de Investigación Biomédica en Red (CIBERCV), CB16/11/00425. C.S.C. is the recipient
of an FPI-SO predoctoral fellowship, BES-2016–076638. M.R.P. was the recipient of a Ph.D. fellowship from
the Italian Ministry of Education, Universities and Research (MIUR). C.P.L. was a recipient of a CNIC Master
Fellowship. We thank N. Vicente for excellent technical support (through grant PEJ16/MED/TL-1593 from
Consejería de Educación, Juventud y Deporte de la Comunidad de Madrid and the European Social Fund). We
thank the Spectroscopy and Nuclear Magnetic Resonance Core Unit at CNIO for access to CD instrumentation
and discussion about protein binding assays. We thank A. Thompson and S. Day for their insights. We thank
all members of the Molecular Mechanics of the Cardiovascular System team for helpful discussions and the
contribution of five anonymous reviewers. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | American Chemical Society (ACS) | es_ES |
dc.type.hasVersion | VoR | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | * |
dc.subject.mesh | Cardiomyopathy, Hypertrophic | es_ES |
dc.subject.mesh | Carrier Proteins | es_ES |
dc.subject.mesh | Humans | es_ES |
dc.subject.mesh | Mutation | es_ES |
dc.subject.mesh | Phenotype | es_ES |
dc.subject.mesh | Sarcomeres | es_ES |
dc.title | Nanomechanical Phenotypes in Cardiac Myosin-Binding Protein C Mutants That Cause Hypertrophic Cardiomyopathy. | es_ES |
dc.type | journal article | es_ES |
dc.rights.license | Atribución 4.0 Internacional | * |
dc.identifier.pubmedID | 34060810 | es_ES |
dc.format.volume | 15 | es_ES |
dc.format.number | 6 | es_ES |
dc.format.page | 10203-10216 | es_ES |
dc.identifier.doi | 10.1021/acsnano.1c02242 | es_ES |
dc.contributor.funder | Ministerio de Ciencia e Innovación (España) | es_ES |
dc.contributor.funder | European Research Area Network on Cardiovascular Diseases | es_ES |
dc.contributor.funder | Comunidad de Madrid (España) | es_ES |
dc.contributor.funder | Stanford Maternal and Child Health Research Institute | es_ES |
dc.contributor.funder | Instituto de Salud Carlos III | es_ES |
dc.contributor.funder | Fundación ProCNIC | es_ES |
dc.contributor.funder | Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España) | es_ES |
dc.contributor.funder | Centro de Investigación Biomédica en Red - CIBERCV (Enfermedades Cardiovasculares) | es_ES |
dc.contributor.funder | Agencia Estatal de Investigación (España) | es_ES |
dc.contributor.funder | Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) | es_ES |
dc.description.peerreviewed | Sí | es_ES |
dc.identifier.e-issn | 1936-086X | es_ES |
dc.relation.publisherversion | 10.1021/acsnano.1c02242 | es_ES |
dc.identifier.journal | ACS nano | es_ES |
dc.repisalud.orgCNIC | CNIC::Grupos de investigación::Mecánica molecular del sistema cardiovascular | es_ES |
dc.repisalud.institucion | CNIC | es_ES |
dc.rights.accessRights | open access | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/BIO2014–54768-P | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/BIO2017–83640-P | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/EIN2019–102966 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/RYC-2014–16604 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/ERA-CVD/ISCIII | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/AC16/00045 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/S2018/NMT-4443 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/IT1254–19 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/RYC-2016–19590 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PGC2018–099321-B-I00 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/SEV-2015–0505 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PEJ16/MED/TL-1593 | es_ES |