Three-dimensional structure of vertebrate cardiac muscle myosin filaments

doi:10.1073/pnas.0708912105

Three-dimensional structure of vertebrate cardiac muscle myosin filaments

*Department of Cell Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655; and
^†Department of Physiology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706

Edited by Hugh E. Huxley, Brandeis University, Waltham, MA, and approved December 13, 2007 (received for review September 19, 2007)

Abstract

Contraction of the heart results from interaction of the myosin and actin filaments. Cardiac myosin filaments consist of the molecular motor myosin II, the sarcomeric template protein, titin, and the cardiac modulatory protein, myosin binding protein C (MyBP-C). Inherited hypertrophic cardiomyopathy (HCM) is a disease caused mainly by mutations in these proteins. The structure of cardiac myosin filaments and the alterations caused by HCM mutations are unknown. We have used electron microscopy and image analysis to determine the three-dimensional structure of myosin filaments from wild-type mouse cardiac muscle and from a MyBP-C knockout model for HCM. Three-dimensional reconstruction of the wild-type filament reveals the conformation of the myosin heads and the organization of titin and MyBP-C at 4 nm resolution. Myosin heads appear to interact with each other intramolecularly, as in off-state smooth muscle myosin [Wendt T, Taylor D, Trybus KM, Taylor K (2001) Proc Natl Acad Sci USA 98:4361–4366], suggesting that all relaxed muscle myosin IIs may adopt this conformation. Titin domains run in an elongated strand along the filament surface, where they appear to interact with part of MyBP-C and with the myosin backbone. In the knockout filament, some of the myosin head interactions are disrupted, suggesting that MyBP-C is important for normal relaxation of the filament. These observations provide key insights into the role of the myosin filament in cardiac contraction, assembly, and disease. The techniques we have developed should be useful in studying the structural basis of other myosin-related HCM diseases.

Footnotes

^‡To whom correspondence should be addressed. E-mail: roger.craig{at}umassmed.edu
Author contributions: M.E.Z. and R.C. designed research; M.E.Z. performed research; M.E.Z., J.L.W., and R.L.M. contributed new reagents/analytic tools; M.E.Z., J.L.W., and R.C. analyzed data; and M.E.Z., J.L.W., and R.C. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The data reported in this paper have been deposited in the EBI Macromolecular Structure Database, www.ebi.ac.uk (accession no. EMD-1465).
This article contains supporting information online at www.pnas.org/cgi/content/full/0708912105/DC1.