DataVXACS NanoPaper
journal article·2021-06-22Open access

Nanomechanical Phenotypes in Cardiac Myosin-Binding Protein C Mutants That Cause Hypertrophic Cardiomyopathy

Carmen Suay-Corredera, Maria Rosaria Pricolo, Diana Velázquez-Carreras, Divya Pathak, Neha Nandwani, Carolina Pimenta-Lopes, David Sánchez-Ortiz, Iñigo Urrutia-Irazabal, Silvia Vilches, Fernando Dominguez, Giulia Frisso, Lorenzo Monserrat, Pablo García-Pavía, David de Sancho, James A. Spudich, Kathleen M. Ruppel, Elías Herrero-Galán, Jorge Alegre-Cebollada

ACS Nano· Volume 15· Issue 6
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Source abstract

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.
Source: openalex_inverted_index · Quality: baseline

Research context

Nanomaterials

OpenAlex topics: Cardiomyopathy and Myosin Studies · Force Microscopy Techniques and Applications · Cellular Mechanics and Interactions

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029, Madrid, Spain

Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, 80131, Naples, Italy

Department of Biochemistry, Stanford University School of Medicine, Stanford, California 94305, United States

Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California 94305, United States

Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, 28222, Madrid, Spain

European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARD-HEART, http://guardheart.ern-net.eu/), 28222, Madrid, Spain

Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), 28029, Madrid, Spain

CEINGE Biotecnologie Avanzate, scarl, 80145, Naples, Italy

Health in Code, 15006, A Coruña, Spain

Universidad Francisco de Vitoria (UFV), 28223, Pozuelo de Alarcón, Madrid, Spain

Polimero eta Material Aurreratuak: Fisika, Kimika eta Teknologia, Kimika Fakultatea, Euskal Herriko Unibertsitatea UPV/EHU, 20018, Donostia-San Sebastián, Spain

Donostia International Physics Center (DIPC), 20018, Donostia-San Sebastián, Spain

Funding

European Regional Development Fund · National Heart, Lung, and Blood Institute · National Institute of General Medical Sciences · Ministero dell???Istruzione, dell???Universit?? e della Ricerca · Ministerio de Ciencia e Innovaci??n · Ministerio de Econom??a y Competitividad · Stanford University · Eusko Jaurlaritza · Consejer??a de Educaci??n, Juventud y Deporte, Comunidad de Madrid · Horizon 2020 Framework Programme · Instituto de Salud Carlos III · European Social Fund · Centro Nacional de Investigaciones Cardiovasculares · Pro CNIC Foundation · Comunidad de Madrid

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