Cryo-EM structures of cardiac muscle α-actin mutants M305L and A331P give insights into the structural mechanisms of hypertrophic cardiomyopathy
Cardiac muscle α-actin is a key protein of the thin filament in the muscle sarcomere that, together with myosin thick filaments, produce force and contraction important for normal heart function. Missense mutations in cardiac muscle α-actin can cause hypertrophic cardiomyopathy, a complex disorder o...
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Elsevier
2024-12-01
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| Series: | European Journal of Cell Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0171933524000773 |
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| author | Hsiang-Ling Huang Andrejus Suchenko Giovanna Grandinetti Mohan K. Balasubramanian Krishna Chinthalapudi Sarah M. Heissler |
| author_facet | Hsiang-Ling Huang Andrejus Suchenko Giovanna Grandinetti Mohan K. Balasubramanian Krishna Chinthalapudi Sarah M. Heissler |
| author_sort | Hsiang-Ling Huang |
| collection | DOAJ |
| description | Cardiac muscle α-actin is a key protein of the thin filament in the muscle sarcomere that, together with myosin thick filaments, produce force and contraction important for normal heart function. Missense mutations in cardiac muscle α-actin can cause hypertrophic cardiomyopathy, a complex disorder of the heart characterized by hypercontractility at the molecular scale that leads to diverse clinical phenotypes. While the clinical aspects of hypertrophic cardiomyopathy have been extensively studied, the molecular mechanisms of missense mutations in cardiac muscle α-actin that cause the disease remain largely elusive. Here we used cryo-electron microscopy to reveal the structures of hypertrophic cardiomyopathy-associated actin mutations M305L and A331P in the filamentous state. We show that the mutations have subtle impacts on the overall architecture of the actin filament with mutation-specific changes in the nucleotide binding cleft active site, interprotomer interfaces, and local changes around the mutation site. This suggests that structural changes induced by M305L and A331P have implications for the positioning of the thin filament protein tropomyosin and the interaction with myosin motors. Overall, this study supports a structural model whereby altered interactions between thick and thin filament proteins contribute to disease mechanisms in hypertrophic cardiomyopathy. |
| format | Article |
| id | doaj-art-a63429944a6a4abfa04f134ebb1f70e1 |
| institution | OA Journals |
| issn | 0171-9335 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | European Journal of Cell Biology |
| spelling | doaj-art-a63429944a6a4abfa04f134ebb1f70e12025-08-20T02:38:58ZengElsevierEuropean Journal of Cell Biology0171-93352024-12-01103415146010.1016/j.ejcb.2024.151460Cryo-EM structures of cardiac muscle α-actin mutants M305L and A331P give insights into the structural mechanisms of hypertrophic cardiomyopathyHsiang-Ling Huang0Andrejus Suchenko1Giovanna Grandinetti2Mohan K. Balasubramanian3Krishna Chinthalapudi4Sarah M. Heissler5Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, OH, USACentre for Mechanochemical Cell Biology and Warwick Medical School, Division of Biomedical Sciences, Coventry, United KingdomDepartment of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, OH, USA; Center for Electron Microscopy and Analysis, College of Engineering, The Ohio State University, Columbus, OH, USACentre for Mechanochemical Cell Biology and Warwick Medical School, Division of Biomedical Sciences, Coventry, United KingdomDepartment of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, OH, USA; Correspondence to: The Ohio State University, Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, 2255 Kenny Road, 5193 PRC, Columbus, OH 43210, USA.Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, OH, USA; Correspondence to: The Ohio State University, Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, 2255 Kenny Road, 5193 PRC, Columbus, OH 43210, USA.Cardiac muscle α-actin is a key protein of the thin filament in the muscle sarcomere that, together with myosin thick filaments, produce force and contraction important for normal heart function. Missense mutations in cardiac muscle α-actin can cause hypertrophic cardiomyopathy, a complex disorder of the heart characterized by hypercontractility at the molecular scale that leads to diverse clinical phenotypes. While the clinical aspects of hypertrophic cardiomyopathy have been extensively studied, the molecular mechanisms of missense mutations in cardiac muscle α-actin that cause the disease remain largely elusive. Here we used cryo-electron microscopy to reveal the structures of hypertrophic cardiomyopathy-associated actin mutations M305L and A331P in the filamentous state. We show that the mutations have subtle impacts on the overall architecture of the actin filament with mutation-specific changes in the nucleotide binding cleft active site, interprotomer interfaces, and local changes around the mutation site. This suggests that structural changes induced by M305L and A331P have implications for the positioning of the thin filament protein tropomyosin and the interaction with myosin motors. Overall, this study supports a structural model whereby altered interactions between thick and thin filament proteins contribute to disease mechanisms in hypertrophic cardiomyopathy.http://www.sciencedirect.com/science/article/pii/S0171933524000773ActinCytoskeletonMutationMyosinHypertrophic cardiomyopathy |
| spellingShingle | Hsiang-Ling Huang Andrejus Suchenko Giovanna Grandinetti Mohan K. Balasubramanian Krishna Chinthalapudi Sarah M. Heissler Cryo-EM structures of cardiac muscle α-actin mutants M305L and A331P give insights into the structural mechanisms of hypertrophic cardiomyopathy European Journal of Cell Biology Actin Cytoskeleton Mutation Myosin Hypertrophic cardiomyopathy |
| title | Cryo-EM structures of cardiac muscle α-actin mutants M305L and A331P give insights into the structural mechanisms of hypertrophic cardiomyopathy |
| title_full | Cryo-EM structures of cardiac muscle α-actin mutants M305L and A331P give insights into the structural mechanisms of hypertrophic cardiomyopathy |
| title_fullStr | Cryo-EM structures of cardiac muscle α-actin mutants M305L and A331P give insights into the structural mechanisms of hypertrophic cardiomyopathy |
| title_full_unstemmed | Cryo-EM structures of cardiac muscle α-actin mutants M305L and A331P give insights into the structural mechanisms of hypertrophic cardiomyopathy |
| title_short | Cryo-EM structures of cardiac muscle α-actin mutants M305L and A331P give insights into the structural mechanisms of hypertrophic cardiomyopathy |
| title_sort | cryo em structures of cardiac muscle α actin mutants m305l and a331p give insights into the structural mechanisms of hypertrophic cardiomyopathy |
| topic | Actin Cytoskeleton Mutation Myosin Hypertrophic cardiomyopathy |
| url | http://www.sciencedirect.com/science/article/pii/S0171933524000773 |
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