The hypertrophic cardiomyopathy-associated A331P actin variant enhances basal contractile activity and elicits resting muscle dysfunction
Summary: Previous studies aimed at defining the mechanistic basis of hypertrophic cardiomyopathy caused by A331P cardiac actin have reported conflicting results. The mutation is located along an actin surface strand, proximal to residues that interact with tropomyosin. These F-actin-tropomyosin asso...
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Elsevier
2025-02-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004225000768 |
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| author | Matthew H. Doran Michael J. Rynkiewicz Evan Despond Meera C. Viswanathan Aditi Madan Kripa Chitre Axel J. Fenwick Duncan Sousa William Lehman John F. Dawson Anthony Cammarato |
| author_facet | Matthew H. Doran Michael J. Rynkiewicz Evan Despond Meera C. Viswanathan Aditi Madan Kripa Chitre Axel J. Fenwick Duncan Sousa William Lehman John F. Dawson Anthony Cammarato |
| author_sort | Matthew H. Doran |
| collection | DOAJ |
| description | Summary: Previous studies aimed at defining the mechanistic basis of hypertrophic cardiomyopathy caused by A331P cardiac actin have reported conflicting results. The mutation is located along an actin surface strand, proximal to residues that interact with tropomyosin. These F-actin-tropomyosin associations are vital for proper contractile inhibition. To help resolve disease pathogenesis, we implemented a multidisciplinary approach. Transgenic Drosophila, expressing A331P actin, displayed skeletal muscle hypercontraction and elevated basal myocardial activity. A331P thin filaments, reconstituted using recombinant human cardiac actin, exhibited higher in vitro myosin-based sliding speeds, exclusively at low Ca2+ concentrations. Cryo-EM-based reconstructions revealed no detectable A331P-related structural perturbations in F-actin. In silico, however, the P331-containing actin surface strand was less mobile and established diminished van der Waal’s attractive forces with tropomyosin, which correlated with greater variability in inhibitory tropomyosin positioning. Such mutation-induced effects potentially elevate resting contractile activity among our models and may stimulate pathology in patients. |
| format | Article |
| id | doaj-art-a021e86005b84e9281b5fa46263355d4 |
| institution | Kabale University |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-a021e86005b84e9281b5fa46263355d42025-02-02T05:29:09ZengElsevieriScience2589-00422025-02-01282111816The hypertrophic cardiomyopathy-associated A331P actin variant enhances basal contractile activity and elicits resting muscle dysfunctionMatthew H. Doran0Michael J. Rynkiewicz1Evan Despond2Meera C. Viswanathan3Aditi Madan4Kripa Chitre5Axel J. Fenwick6Duncan Sousa7William Lehman8John F. Dawson9Anthony Cammarato10Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian & Avedisian School of Medicine, 72 E. Concord St, Boston, MA 02118, USADepartment of Pharmacology, Physiology & Biophysics, Boston University Chobanian & Avedisian School of Medicine, 72 E. Concord St, Boston, MA 02118, USADepartment Molecular and Cellular Biology, University of Guelph, 50 Stone Road E, Guelph, ON N1G 2W1, CanadaDepartment of Medicine, Division of Cardiology, Johns Hopkins University, 720 Rutland Avenue, Baltimore, MD 21205, USADepartment of Medicine, Division of Cardiology, Johns Hopkins University, 720 Rutland Avenue, Baltimore, MD 21205, USADepartment of Medicine, Division of Cardiology, Johns Hopkins University, 720 Rutland Avenue, Baltimore, MD 21205, USADepartment of Medicine, Division of Cardiology, Johns Hopkins University, 720 Rutland Avenue, Baltimore, MD 21205, USADepartment of Biophysics, Johns Hopkins University, 725 N. Wolfe Street, Baltimore, MD 21205, USADepartment of Pharmacology, Physiology & Biophysics, Boston University Chobanian & Avedisian School of Medicine, 72 E. Concord St, Boston, MA 02118, USADepartment Molecular and Cellular Biology, University of Guelph, 50 Stone Road E, Guelph, ON N1G 2W1, Canada; Corresponding authorDepartment of Medicine, Division of Cardiology, Johns Hopkins University, 720 Rutland Avenue, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA; Corresponding authorSummary: Previous studies aimed at defining the mechanistic basis of hypertrophic cardiomyopathy caused by A331P cardiac actin have reported conflicting results. The mutation is located along an actin surface strand, proximal to residues that interact with tropomyosin. These F-actin-tropomyosin associations are vital for proper contractile inhibition. To help resolve disease pathogenesis, we implemented a multidisciplinary approach. Transgenic Drosophila, expressing A331P actin, displayed skeletal muscle hypercontraction and elevated basal myocardial activity. A331P thin filaments, reconstituted using recombinant human cardiac actin, exhibited higher in vitro myosin-based sliding speeds, exclusively at low Ca2+ concentrations. Cryo-EM-based reconstructions revealed no detectable A331P-related structural perturbations in F-actin. In silico, however, the P331-containing actin surface strand was less mobile and established diminished van der Waal’s attractive forces with tropomyosin, which correlated with greater variability in inhibitory tropomyosin positioning. Such mutation-induced effects potentially elevate resting contractile activity among our models and may stimulate pathology in patients.http://www.sciencedirect.com/science/article/pii/S2589004225000768Biological sciencesCell biologyMolecular interactionMolecular StructureStructural biology |
| spellingShingle | Matthew H. Doran Michael J. Rynkiewicz Evan Despond Meera C. Viswanathan Aditi Madan Kripa Chitre Axel J. Fenwick Duncan Sousa William Lehman John F. Dawson Anthony Cammarato The hypertrophic cardiomyopathy-associated A331P actin variant enhances basal contractile activity and elicits resting muscle dysfunction iScience Biological sciences Cell biology Molecular interaction Molecular Structure Structural biology |
| title | The hypertrophic cardiomyopathy-associated A331P actin variant enhances basal contractile activity and elicits resting muscle dysfunction |
| title_full | The hypertrophic cardiomyopathy-associated A331P actin variant enhances basal contractile activity and elicits resting muscle dysfunction |
| title_fullStr | The hypertrophic cardiomyopathy-associated A331P actin variant enhances basal contractile activity and elicits resting muscle dysfunction |
| title_full_unstemmed | The hypertrophic cardiomyopathy-associated A331P actin variant enhances basal contractile activity and elicits resting muscle dysfunction |
| title_short | The hypertrophic cardiomyopathy-associated A331P actin variant enhances basal contractile activity and elicits resting muscle dysfunction |
| title_sort | hypertrophic cardiomyopathy associated a331p actin variant enhances basal contractile activity and elicits resting muscle dysfunction |
| topic | Biological sciences Cell biology Molecular interaction Molecular Structure Structural biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004225000768 |
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