Deciphering the super relaxed state of human β-cardiac myosin and the mode of action of mavacamten from myosin molecules to muscle fibers
Abstract
Mutations in β-cardiac myosin, the predominant motor protein for human heart contraction, can alter power output and cause cardiomyopathy. However, measurements of the intrinsic force, velocity, and ATPase activity of myosin have not provided a consistent mechanism to link mutations to muscle pathology. An alternative model posits that mutations in myosin affect the stability of a sequestered, super relaxed state (SRX) of the protein with very slow ATP hydrolysis and thereby change the number of myosin heads accessible to actin. Here we show that purified human β-cardiac myosin exists partly in an SRX and may in part correspond to a folded-back conformation of myosin heads observed in muscle fibers around the thick filament backbone. Mutations that cause hypertrophic cardiomyopathy destabilize this state, while the small molecule mavacamten promotes it. Furthermore, these findings provide a biochemical and structural link between the genetics and physiology of cardiomyopathy with implications for therapeutic strategies.
- Authors:
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; National Institutes of Health (NIH)
- OSTI Identifier:
- 1464331
- Alternate Identifier(s):
- OSTI ID: 1470476
- Grant/Contract Number:
- AC02-06CH11357; GM33289; HL117138; AR062279; HL084553; P41 GM103622
- Resource Type:
- Published Article
- Journal Name:
- Proceedings of the National Academy of Sciences of the United States of America
- Additional Journal Information:
- Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Volume: 115 Journal Issue: 35; Journal ID: ISSN 0027-8424
- Publisher:
- National Academy of Sciences
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; myosin; super relaxed state; interacting heads motif; cardiac inhibitor; mavacamten
Citation Formats
Anderson, Robert L., Trivedi, Darshan V., Sarkar, Saswata S., Henze, Marcus, Ma, Weikang, Gong, Henry, Rogers, Christopher S., Gorham, Joshua M., Wong, Fiona L., Morck, Makenna M., Seidman, Jonathan G., Ruppel, Kathleen M., Irving, Thomas C., Cooke, Roger, Green, Eric M., and Spudich, James A. Deciphering the super relaxed state of human β-cardiac myosin and the mode of action of mavacamten from myosin molecules to muscle fibers. United States: N. p., 2018.
Web. doi:10.1073/pnas.1809540115.
Anderson, Robert L., Trivedi, Darshan V., Sarkar, Saswata S., Henze, Marcus, Ma, Weikang, Gong, Henry, Rogers, Christopher S., Gorham, Joshua M., Wong, Fiona L., Morck, Makenna M., Seidman, Jonathan G., Ruppel, Kathleen M., Irving, Thomas C., Cooke, Roger, Green, Eric M., & Spudich, James A. Deciphering the super relaxed state of human β-cardiac myosin and the mode of action of mavacamten from myosin molecules to muscle fibers. United States. https://doi.org/10.1073/pnas.1809540115
Anderson, Robert L., Trivedi, Darshan V., Sarkar, Saswata S., Henze, Marcus, Ma, Weikang, Gong, Henry, Rogers, Christopher S., Gorham, Joshua M., Wong, Fiona L., Morck, Makenna M., Seidman, Jonathan G., Ruppel, Kathleen M., Irving, Thomas C., Cooke, Roger, Green, Eric M., and Spudich, James A. Mon .
"Deciphering the super relaxed state of human β-cardiac myosin and the mode of action of mavacamten from myosin molecules to muscle fibers". United States. https://doi.org/10.1073/pnas.1809540115.
@article{osti_1464331,
title = {Deciphering the super relaxed state of human β-cardiac myosin and the mode of action of mavacamten from myosin molecules to muscle fibers},
author = {Anderson, Robert L. and Trivedi, Darshan V. and Sarkar, Saswata S. and Henze, Marcus and Ma, Weikang and Gong, Henry and Rogers, Christopher S. and Gorham, Joshua M. and Wong, Fiona L. and Morck, Makenna M. and Seidman, Jonathan G. and Ruppel, Kathleen M. and Irving, Thomas C. and Cooke, Roger and Green, Eric M. and Spudich, James A.},
abstractNote = {Mutations in β-cardiac myosin, the predominant motor protein for human heart contraction, can alter power output and cause cardiomyopathy. However, measurements of the intrinsic force, velocity, and ATPase activity of myosin have not provided a consistent mechanism to link mutations to muscle pathology. An alternative model posits that mutations in myosin affect the stability of a sequestered, super relaxed state (SRX) of the protein with very slow ATP hydrolysis and thereby change the number of myosin heads accessible to actin. Here we show that purified human β-cardiac myosin exists partly in an SRX and may in part correspond to a folded-back conformation of myosin heads observed in muscle fibers around the thick filament backbone. Mutations that cause hypertrophic cardiomyopathy destabilize this state, while the small molecule mavacamten promotes it. Furthermore, these findings provide a biochemical and structural link between the genetics and physiology of cardiomyopathy with implications for therapeutic strategies.},
doi = {10.1073/pnas.1809540115},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 35,
volume = 115,
place = {United States},
year = {Mon Aug 13 00:00:00 EDT 2018},
month = {Mon Aug 13 00:00:00 EDT 2018}
}
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https://doi.org/10.1073/pnas.1809540115
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Works referenced in this record:
Blebbistatin Stabilizes the Helical Order of Myosin Filaments by Promoting the Switch 2 Closed State
journal, October 2008
- Zhao, Fa-Qing; Padrón, Raúl; Craig, Roger
- Biophysical Journal, Vol. 95, Issue 7
Atomic model of a myosin filament in the relaxed state
journal, August 2005
- Woodhead, John L.; Zhao, Fa-Qing; Craig, Roger
- Nature, Vol. 436, Issue 7054
Helical Order in Tarantula Thick Filaments Requires the “Closed” Conformation of the Myosin Head
journal, September 2004
- Zoghbi, M. E.; Woodhead, J. L.; Craig, R.
- Journal of Molecular Biology, Vol. 342, Issue 4
The myosin mesa and a possible unifying hypothesis for the molecular basis of human hypertrophic cardiomyopathy
journal, January 2015
- Spudich, James A.
- Biochemical Society Transactions, Vol. 43, Issue 1
Myosin-binding protein C corrects an intrinsic inhomogeneity in cardiac excitation-contraction coupling
journal, February 2015
- Previs, Michael J.; Prosser, Benjamin L.; Mun, Ji Young
- Science Advances, Vol. 1, Issue 1
Light-chain phosphorylation controls the conformation of vertebrate non-muscle and smooth muscle myosin molecules
journal, March 1983
- Craig, Roger; Smith, Robin; Kendrick-Jones, John
- Nature, Vol. 302, Issue 5907
Time-resolved X-ray diffraction studies of the myosin layer-line reflections during muscle contraction
journal, July 1982
- Huxley, H. E.; Faruqi, A. R.; Kress, M.
- Journal of Molecular Biology, Vol. 158, Issue 4
Spectroscopic Studies of the Super Relaxed State of Skeletal Muscle
journal, August 2016
- Nogara, Leonardo; Naber, Nariman; Pate, Edward
- PLOS ONE, Vol. 11, Issue 8
Calcium-dependent structural changes in scallop heavy meromyosin
journal, March 2001
- Stafford, W. F.; Jacobsen, M. P.; Woodhead, J.
- Journal of Molecular Biology, Vol. 307, Issue 1
The Filament Lattice of Striated Muscle
journal, April 1998
- Millman, Barry M.
- Physiological Reviews, Vol. 78, Issue 2
Slow Myosin ATP Turnover in the Super-Relaxed State in Tarantula Muscle
journal, September 2011
- Naber, Nariman; Cooke, Roger; Pate, Edward
- Journal of Molecular Biology, Vol. 411, Issue 5
Crystal structures of human cardiac beta-myosin II S2- provide insight into the functional role of the S2 subfragment
journal, November 2006
- Blankenfeldt, W.; Thoma, N. H.; Wray, J. S.
- Proceedings of the National Academy of Sciences, Vol. 103, Issue 47
Myosin subfragment-1 is sufficient to move actin filaments in vitro
journal, August 1987
- Toyoshima, Yoko Yano; Kron, Stephen J.; McNally, Elizabeth M.
- Nature, Vol. 328, Issue 6130
Three-Dimensional Reconstruction of Tarantula Myosin Filaments Suggests How Phosphorylation May Regulate Myosin Activity
journal, December 2008
- Alamo, Lorenzo; Wriggers, Willy; Pinto, Antonio
- Journal of Molecular Biology, Vol. 384, Issue 4
Structure of the myosin projections on native thick filaments from vertebrate skeletal muscle
journal, August 1984
- Knight, Peter; Trinick, John
- Journal of Molecular Biology, Vol. 177, Issue 3
Omecamtiv mercabil and blebbistatin modulate cardiac contractility by perturbing the regulatory state of the myosin filament: Myosin filament regulation in heart muscle
journal, November 2017
- Kampourakis, Thomas; Zhang, Xuemeng; Sun, Yin-Biao
- The Journal of Physiology, Vol. 596, Issue 1
Crystal Structure of a Vertebrate Smooth Muscle Myosin Motor Domain and Its Complex with the Essential Light Chain
journal, September 1998
- Dominguez, Roberto; Freyzon, Yelena; Trybus, Kathleen M.
- Cell, Vol. 94, Issue 5
Atomic model of the human cardiac muscle myosin filament
journal, December 2012
- AL-Khayat, H. A.; Kensler, R. W.; Squire, J. M.
- Proceedings of the National Academy of Sciences, Vol. 110, Issue 1
Multidimensional structure-function relationships in human β-cardiac myosin from population-scale genetic variation
journal, May 2016
- Homburger, Julian R.; Green, Eric M.; Caleshu, Colleen
- Proceedings of the National Academy of Sciences, Vol. 113, Issue 24
Early-Onset Hypertrophic Cardiomyopathy Mutations Significantly Increase the Velocity, Force, and Actin-Activated ATPase Activity of Human β-Cardiac Myosin
journal, December 2016
- Adhikari, Arjun S.; Kooiker, Kristina B.; Sarkar, Saswata S.
- Cell Reports, Vol. 17, Issue 11
Molecular mechanisms of cardiomyopathy phenotypes associated with myosin light chain mutations
journal, September 2015
- Huang, Wenrui; Szczesna-Cordary, Danuta
- Journal of Muscle Research and Cell Motility, Vol. 36, Issue 6
A Mouse Model of Familial Hypertrophic Cardiomyopathy
journal, May 1996
- Geisterfer-Lowrance, A. A. T.; Christe, M.; Conner, D. A.
- Science, Vol. 272, Issue 5262
Contractility parameters of human β-cardiac myosin with the hypertrophic cardiomyopathy mutation R403Q show loss of motor function
journal, October 2015
- Nag, Suman; Sommese, Ruth F.; Ujfalusi, Zoltan
- Science Advances, Vol. 1, Issue 9
Ablation of cardiac myosin binding protein-C disrupts the super-relaxed state of myosin in murine cardiomyocytes
journal, May 2016
- McNamara, James W.; Li, Amy; Smith, Nicola J.
- Journal of Molecular and Cellular Cardiology, Vol. 94
Visualization of Head–Head Interactions in the Inhibited State of Smooth Muscle Myosin
journal, December 1999
- Wendt, Thomas; Taylor, Dianne; Messier, Terri
- The Journal of Cell Biology, Vol. 147, Issue 7
Dynamics of left ventricular emptying in hypertrophic subaortic stenosis
journal, January 1967
- Wilson, W. Stanley; Criley, J. Michael; Ross, Richard S.
- American Heart Journal, Vol. 73, Issue 1
Understanding Cardiomyopathy Phenotypes Based on the Functional Impact of Mutations in the Myosin Motor
journal, July 2012
- Moore, Jeffrey R.; Leinwand, Leslie; Warshaw, David M.
- Circulation Research, Vol. 111, Issue 3
Titin strain contributes to the Frank–Starling law of the heart by structural rearrangements of both thin- and thick-filament proteins
journal, February 2016
- Ait-Mou, Younss; Hsu, Karen; Farman, Gerrie P.
- Proceedings of the National Academy of Sciences, Vol. 113, Issue 8
Temperature and Ligand Dependence of Conformation and Helical Order in Myosin Filaments
journal, January 2003
- Xu, S.; Offer, G.; Gu, J.
- Biochemistry, Vol. 42, Issue 2
The Myosin Inhibitor Blebbistatin Stabilizes the Super-Relaxed State in Skeletal Muscle
journal, October 2014
- Wilson, Clyde; Naber, Nariman; Pate, Edward
- Biophysical Journal, Vol. 107, Issue 7
Role of the Tail in the Regulated State of Myosin 2
journal, May 2011
- Jung, Hyun Suk; Billington, Neil; Thirumurugan, Kavitha
- Journal of Molecular Biology, Vol. 408, Issue 5
Phosphorylation of myosin regulatory light chain controls myosin head conformation in cardiac muscle
journal, August 2015
- Kampourakis, Thomas; Irving, Malcolm
- Journal of Molecular and Cellular Cardiology, Vol. 85
Structures of Smooth Muscle Myosin and Heavy Meromyosin in the Folded, Shutdown State
journal, October 2007
- Burgess, Stan A.; Yu, Shuizi; Walker, Matt L.
- Journal of Molecular Biology, Vol. 372, Issue 5
A molecular basis for familial hypertrophic cardiomyopathy: A β cardiac myosin heavy chain gene missense mutation
journal, September 1990
- Geisterfer-Lowrance, Anja A. T.; Kass, Susan; Tanigawa, Gary
- Cell, Vol. 62, Issue 5
Myosin binding protein-C activates thin filaments and inhibits thick filaments in heart muscle cells
journal, December 2014
- Kampourakis, Thomas; Yan, Ziqian; Gautel, Mathias
- Proceedings of the National Academy of Sciences, Vol. 111, Issue 52
The role of super-relaxed myosin in skeletal and cardiac muscle
journal, December 2014
- McNamara, James W.; Li, Amy; dos Remedios, Cristobal G.
- Biophysical Reviews, Vol. 7, Issue 1
Force generation by skeletal muscle is controlled by mechanosensing in myosin filaments
journal, November 2015
- Linari, Marco; Brunello, Elisabetta; Reconditi, Massimo
- Nature, Vol. 528, Issue 7581
A small-molecule modulator of cardiac myosin acts on multiple stages of the myosin chemomechanical cycle
journal, August 2017
- Kawas, Raja F.; Anderson, Robert L.; Ingle, Sadie R. Bartholomew
- Journal of Biological Chemistry, Vol. 292, Issue 40
Spare the rod, spoil the regulation: Necessity for a myosin rod
journal, January 1997
- Trybus, K. M.; Freyzon, Y.; Faust, L. Z.
- Proceedings of the National Academy of Sciences, Vol. 94, Issue 1
The role of the myosin ATPase activity in adaptive thermogenesis by skeletal muscle
journal, March 2011
- Cooke, Roger
- Biophysical Reviews, Vol. 3, Issue 1
A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice
journal, February 2016
- Green, E. M.; Wakimoto, H.; Anderson, R. L.
- Science, Vol. 351, Issue 6273
Mavacamten stabilizes an autoinhibited state of two-headed cardiac myosin
journal, July 2018
- Rohde, John A.; Roopnarine, Osha; Thomas, David D.
- Proceedings of the National Academy of Sciences, Vol. 115, Issue 32
Three-dimensional structure of vertebrate cardiac muscle myosin filaments
journal, February 2008
- Zoghbi, M. E.; Woodhead, J. L.; Moss, R. L.
- Proceedings of the National Academy of Sciences, Vol. 105, Issue 7
Effects of myosin variants on interacting-heads motif explain distinct hypertrophic and dilated cardiomyopathy phenotypes
journal, June 2017
- Alamo, Lorenzo; Ware, James S.; Pinto, Antonio
- eLife, Vol. 6
Myosin light chain phosphorylation enhances contraction of heart muscle via structural changes in both thick and thin filaments
journal, May 2016
- Kampourakis, Thomas; Sun, Yin-Biao; Irving, Malcolm
- Proceedings of the National Academy of Sciences, Vol. 113, Issue 21
Conformational states of smooth muscle myosin. Effects of light chain phosphorylation and ionic strength.
journal, July 1984
- Trybus, K. M.; Lowey, S.
- Journal of Biological Chemistry, Vol. 259, Issue 13
Hypertrophic and Dilated Cardiomyopathy: Four Decades of Basic Research on Muscle Lead to Potential Therapeutic Approaches to These Devastating Genetic Diseases
journal, March 2014
- Spudich, James A.
- Biophysical Journal, Vol. 106, Issue 6
Biophysical properties of human β-cardiac myosin with converter mutations that cause hypertrophic cardiomyopathy
journal, February 2017
- Kawana, Masataka; Sarkar, Saswata S.; Sutton, Shirley
- Science Advances, Vol. 3, Issue 2
Hypertrophic cardiomyopathy and the myosin mesa: viewing an old disease in a new light
journal, July 2017
- Trivedi, Darshan V.; Adhikari, Arjun S.; Sarkar, Saswata S.
- Biophysical Reviews, Vol. 10, Issue 1
The M·ADP·Pi State Is Required for Helical Order in the Thick Filaments of Skeletal Muscle
journal, November 1999
- Xu, S.; Gu, J.; Rhodes, T.
- Biophysical Journal, Vol. 77, Issue 5
Regulation of Contraction by the Thick Filaments in Skeletal Muscle
journal, December 2017
- Irving, Malcolm
- Biophysical Journal, Vol. 113, Issue 12
Three-dimensional image reconstruction of dephosphorylated smooth muscle heavy meromyosin reveals asymmetry in the interaction between myosin heads and placement of subfragment 2
journal, April 2001
- Wendt, T.; Taylor, D.; Trybus, K. M.
- Proceedings of the National Academy of Sciences, Vol. 98, Issue 8
Myosin ATP turnover rate is a mechanism involved in thermogenesis in resting skeletal muscle fibers
journal, December 2009
- Stewart, M. A.; Franks-Skiba, K.; Chen, S.
- Proceedings of the National Academy of Sciences, Vol. 107, Issue 1
The myosin mesa and the basis of hypercontractility caused by hypertrophic cardiomyopathy mutations
journal, May 2017
- Nag, Suman; Trivedi, Darshan V.; Sarkar, Saswata S.
- Nature Structural & Molecular Biology, Vol. 24, Issue 6
Motion of myosin head domains during activation and force development in skeletal muscle
journal, April 2011
- Reconditi, M.; Brunello, E.; Linari, M.
- Proceedings of the National Academy of Sciences, Vol. 108, Issue 17
Effects of hypertrophic and dilated cardiomyopathy mutations on power output by human β-cardiac myosin
journal, January 2016
- Spudich, James A.; Aksel, Tural; Bartholomew, Sadie R.
- The Journal of Experimental Biology, Vol. 219, Issue 2
Myosin filament activation in the heart is tuned to the mechanical task
journal, March 2017
- Reconditi, Massimo; Caremani, Marco; Pinzauti, Francesca
- Proceedings of the National Academy of Sciences, Vol. 114, Issue 12
Single-Molecule Mechanics of R403Q Cardiac Myosin Isolated From the Mouse Model of Familial Hypertrophic Cardiomyopathy
journal, April 2000
- Tyska, M. J.; Hayes, E.; Giewat, M.
- Circulation Research, Vol. 86, Issue 7
Effect of substrate on freeze-dried and shadowed protein structures
journal, May 1982
- Trinick, J.; Elliott, A.
- Journal of Microscopy, Vol. 126, Issue 2
A New State of Cardiac Myosin with Very Slow ATP Turnover: A Potential Cardioprotective Mechanism in the Heart
journal, April 2011
- Hooijman, Pleuni; Stewart, Melanie A.; Cooke, Roger
- Biophysical Journal, Vol. 100, Issue 8
The Genetic Basis for Cardiomyopathy
journal, February 2001
- Seidman, J. G.; Seidman, Christine
- Cell, Vol. 104, Issue 4
Conserved Intramolecular Interactions Maintain Myosin Interacting-Heads Motifs Explaining Tarantula Muscle Super-Relaxed State Structural Basis
journal, March 2016
- Alamo, Lorenzo; Qi, Dan; Wriggers, Willy
- Journal of Molecular Biology, Vol. 428, Issue 6
Mechanisms of the Frank-Starling Law of the Heart: The Beat Goes On
journal, December 2007
- John Solaro, R.
- Biophysical Journal, Vol. 93, Issue 12
Cardiac muscle function across the natural history of a genetic minipig model of hypertrophic cardiomyopathy
journal, November 2017
- Henze, Marcus; Anderson, Robert; Wong, Fiona
- Journal of Molecular and Cellular Cardiology, Vol. 112