Multidimensional structure-function relationships in human β-cardiac myosin from population-scale genetic variation

Authors:
Publisher website
Google Scholar
Abstract
Myosin motors are the fundamental force-generating elements of muscle contraction. Variation in the human β-cardiac myosin heavy chain gene (MYH7) can lead to hypertrophic cardiomyopathy (HCM), a heritable disease characterized by cardiac hypertrophy, heart failure, and sudden cardiac death. How specific myosin variants alter motor function or clinical expression of disease remains incompletely understood. Here, we combine structural models of myosin from multiple stages of its chemomechanical cycle, exome sequencing data from two population cohorts of 60,706 and 42,930 individuals, and genetic and phenotypic data from 2,913 patients with HCM to identify regions of disease enrichment within β-cardiac myosin. We first developed computational models of the human β-cardiac myosin protein before and after the myosin power stroke. Then, using a spatial scan statistic modified to analyze genetic variation in protein 3D space, we found significant enrichment of disease-associated variants in the converter, a kinetic domain that transduces force from the catalytic domain to the lever arm to accomplish the power stroke. Focusing our analysis on surface-exposed residues, we identified a larger region significantly enriched for disease-associated variants that contains both the converter domain and residues on a single flat surface on the myosin head described as the myosin mesa. Notably, patients with HCM with variants in the enriched regions have earlier disease onset than patients who have HCM with variants elsewhere. Our study provides a model for integrating protein structure, large-scale genetic sequencing, and detailed phenotypic data to reveal insight into time-shifted protein structures and genetic disease. Significance Genetic variants in human β-cardiac myosin, which causes muscle contraction in the heart, can lead to hypertrophic cardiomyopathy (HCM), an inherited heart disease that can cause sudden death. New technologies have generated sequence data for large numbers of patients with HCM and unaffected individuals. In this study, we compare the protein structural locations of genetic variants of patients with HCM and the general population to identify spatial regions of the myosin that have a higher than expected proportion of genetic variants associated with HCM and earlier age at diagnosis. In addition, we develop new methods to interrogate the localization of genetic changes in protein structures. Our study demonstrates the power of combining clinical, genetic, and structural data to gain insight into Mendelian disease.
All Related Versions
Funding Information
  • Stanford University (Stanford Graduate Fellowship)
  • HHS | National Institutes of Health (F32 HL123247)
  • HHS | National Institutes of Health (U01 HG007708)

This publication has 52 references indexed in Scilit: