2026-05-13T08:35:28Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/151682024-09-27T09:31:05Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Suay-Corredera, Carmen author Pricolo, Maria Rosaria author Velázquez-Carreras, Diana author Pathak, Divya author Nandwani, Neha author Pimenta-Lopes, Carolina author Sánchez-Ortiz, David author Urrutia-Irazabal, Iñigo author Vilches, Silvia author Dominguez, Fernando author Frisso, Giulia author Monserrat, Lorenzo author García-Pavía, Pablo author de Sancho, David author Spudich, James A author Ruppel, Kathleen M author Herrero-Galán, Elías author Alegre-Cebollada, Jorge author 2021 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. ACS Nano . 2021 Jun 22;15(6):10203-10216. 10.1021/acsnano.1c02242 1936-086X ACS nano 34060810 http://hdl.handle.net/20.500.12105/15168 Nanomechanical Phenotypes in Cardiac Myosin-Binding Protein C Mutants That Cause Hypertrophic Cardiomyopathy.