Effects of myosin variants explain distinct cardiomyopathy phenotypes

Lorenzo Alamo1, James S. Ware2,3,4, Antonio Pinto1, Richard E Gillilan5, Jonathan G. Seidman4, Christine E. Seidman4,6 & Raúl Padrón1

1Centro de Biología Estructural “Humberto Fernández-Morán”, Instituto Venezolano de Investigaciones Científicas, Caracas, Venezuela; 2National Heart and Lung Institute and MRC London Institute for Medical Sciences, Imperial College London, London, United Kingdom; 3NIHR Cardiovascular Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, London, United Kingdom; 4Department of Genetics, Harvard Medical School, Boston, United States; 5Macromolecular Diffraction Facility, Cornell High Energy Synchrotron Source, Ithaca, United States; 6Cardiovascular Division, Brigham and Women’s Hospital and Howard Hughes Medical Institute, Boston, United States

Email: raul.padron@gmail.com   Padrón lab: http://www.raul-padron.org/lab/

Abstract:  Cardiac b-myosin variants cause hypertrophic (HCM) or dilated (DCM) cardiomyopathy by disrupting sarcomere contraction and relaxation. The locations of variants on isolated myosin head structures predict contractility effects but not the prominent relaxation and energetic deficits that characterize HCM. During relaxation, pairs of myosins form interacting-heads motif (IHM) structures that with other sarcomere proteins establish an energy-saving, super-relaxed (SRX) state. Using a human b-cardiac myosin IHM quasi-atomic model (PDB 5TBY), we defined interactions sites between adjacent myosin heads and associated protein partners, and then analyzed rare variants from 6112 HCM and 1315 DCM patients and 33,370 ExAC controls. HCM variants, 72% that changed electrostatic charges, disproportionately altered IHM interaction residues (expected 23%; HCM 54%, p=2.6×10-19; DCM 26%, p=0.66; controls 20%, p=0.23). HCM variant locations predict impaired IHM formation and stability, and attenuation of the SRX state – accounting for altered contractility, reduced diastolic relaxation, and increased energy consumption, that fully characterizes HCM pathogenesis.

eLife 2017;6:e24634 https://elifesciences.org/articles/24634  doi: 10.7554/eLife.24634

Article PDF download: file elife-24634-figures-v1.pdf Figures PDF download: elife-24634-v1.pdf

Graphical summary: graphical_summary.jpg

Top row: Sections of relaxed healthy, HCM and DCM hearts. Bottom row: Human beta-cardiac myosin interacting heads motif (IHM) PDB 5TBY (left) showing the impact of DCM (center) and HCM (right) variants (color spheres) on the IHM structure. Code to reproduce analyses presented in Alamo et al, eLife 2017: https://github.com/jamesware/eLife_Alamo2017

Human beta-cardiac myosin interacting heads motif (IHM) PDB 5TBY:

RCSB Protein Data Bank: http://www.rcsb.org/pdb/explore/structureCluster.do?structureId=5TBY

Protein Data bank in Europe: https://www.ebi.ac.uk/pdbe/entry/pdb/5tby

3D_EM Data Navigator: https://pdbj.org/emnavi/emnavi_detail.php?lgc=1&id=5tby

Yorodumi: https://pdbj.org/emnavi/quick.php?id=pdb-5tby

Spider proteins offer new insight into human heart conditions (Imperial College News)  by Ryan O´Hare

Lessons from a Tarantula: Spider muscles reveals details about mutations that disrupt heart relaxation (Harvard Medical School News)   by Hanae Armitage

Lessons the Tarantula: Spider muscles reveals details about mutations that disrupt heart relaxation (HHMI News) by Hanae Armitage

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