Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

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

Julian R. Homburger, Eric M. Green, Colleen Caleshu, Margaret Sunitha, Rebecca Taylor, Kathleen M. Ruppel, Raghu Metpally, SHaRe Investigators, Steven D. Colan, Michelle Michels, Sharlene Day, Iacopo Olivotto, Carlos D. Bustamante, Frederick Dewey, Carolyn Y. Ho, James A. Spudich, Euan A. Ashley
doi: https://doi.org/10.1101/039321
Julian R. Homburger
1Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Eric M. Green
2MyoKardia, Inc. South San Francisco, CA 94080.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Colleen Caleshu
3Stanford Center for Inherited Cardiovascular Disease, Stanford University, Stanford, CA 94305.
4Division of Medical Genetics, Stanford University, Stanford, CA 94305.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Margaret Sunitha
5Institute for Stem Cell Biology and Regenerative Medicine, Bangalore 560065, India.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Rebecca Taylor
6Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kathleen M. Ruppel
6Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305.
7Department of Pediatrics (Cardiology), Stanford University School of Medicine, Stanford, CA 94305.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Raghu Metpally
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Steven D. Colan
9Department of Cardiology, Boston Children’s Hospital, Boston, MA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michelle Michels
10Department of Cardiology, Erasmus MC, Rotterdam, the Netherlands.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sharlene Day
11Cardiovascular Division, Department of Internal Medicine, University of Michigan, Ann Arbor, MI
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Iacopo Olivotto
12Referral Center for Cardiomyopathies, Careggi University Hospital, Florence, Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Carlos D. Bustamante
1Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305.
13Department of Biomedical Data Sciences, Stanford University, Stanford, CA 94305.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Frederick Dewey
14Regeneron Inc., Tarrytown, NY.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Carolyn Y. Ho
15Brigham and Women’s Hospital, Boston, MA.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
James A. Spudich
5Institute for Stem Cell Biology and Regenerative Medicine, Bangalore 560065, India.
6Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: euan@stanford.edu jspudich@stanford.edu
Euan A. Ashley
1Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305.
3Stanford Center for Inherited Cardiovascular Disease, Stanford University, Stanford, CA 94305.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: euan@stanford.edu jspudich@stanford.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

Myosin motors are the fundamental force-generating element of muscle contraction. Variation in the human β-cardiac myosin 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 population cohorts of 60,706 and 42,930 individuals, and genetic and phenotypic data from 2,913 HCM patients to elucidate novel structure-function relationships 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 three-dimensional 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 another region enriched for disease-associated variants that contains both the converter domain and residues on a single flat surface on the myosin head described as a myosin mesa. This surface is prominent in the pre-stroke model, but substantially reduced in size following the power stroke. Notably, HCM patients with variants in the enriched regions have earlier presentation and worse outcome than those with variants in other regions. In summary, this study provides a model for the combination of protein structure, large-scale genetic sequencing and detailed phenotypic data to reveal insight into time-shifted protein structures and genetic disease.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Back to top
PreviousNext
Posted February 09, 2016.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Multi-dimensional structure function relationships in human β-cardiac myosin from population scale genetic variation
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Multi-dimensional structure function relationships in human β-cardiac myosin from population scale genetic variation
Julian R. Homburger, Eric M. Green, Colleen Caleshu, Margaret Sunitha, Rebecca Taylor, Kathleen M. Ruppel, Raghu Metpally, SHaRe Investigators, Steven D. Colan, Michelle Michels, Sharlene Day, Iacopo Olivotto, Carlos D. Bustamante, Frederick Dewey, Carolyn Y. Ho, James A. Spudich, Euan A. Ashley
bioRxiv 039321; doi: https://doi.org/10.1101/039321
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
Multi-dimensional structure function relationships in human β-cardiac myosin from population scale genetic variation
Julian R. Homburger, Eric M. Green, Colleen Caleshu, Margaret Sunitha, Rebecca Taylor, Kathleen M. Ruppel, Raghu Metpally, SHaRe Investigators, Steven D. Colan, Michelle Michels, Sharlene Day, Iacopo Olivotto, Carlos D. Bustamante, Frederick Dewey, Carolyn Y. Ho, James A. Spudich, Euan A. Ashley
bioRxiv 039321; doi: https://doi.org/10.1101/039321

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Genomics
Subject Areas
All Articles
  • Animal Behavior and Cognition (3506)
  • Biochemistry (7348)
  • Bioengineering (5324)
  • Bioinformatics (20266)
  • Biophysics (10020)
  • Cancer Biology (7744)
  • Cell Biology (11306)
  • Clinical Trials (138)
  • Developmental Biology (6437)
  • Ecology (9954)
  • Epidemiology (2065)
  • Evolutionary Biology (13325)
  • Genetics (9361)
  • Genomics (12587)
  • Immunology (7702)
  • Microbiology (19027)
  • Molecular Biology (7444)
  • Neuroscience (41049)
  • Paleontology (300)
  • Pathology (1230)
  • Pharmacology and Toxicology (2138)
  • Physiology (3161)
  • Plant Biology (6861)
  • Scientific Communication and Education (1273)
  • Synthetic Biology (1897)
  • Systems Biology (5313)
  • Zoology (1089)