The myosin mesa and the basis of hypercontractility caused by hypertrophic cardiomyopathy mutations

被引:148
作者
Nag, Suman [1 ]
Trivedi, Darshan V. [1 ]
Sarkar, Saswata S. [1 ]
Adhikari, Arjun S. [1 ]
Sunitha, Margaret S. [2 ]
Sutton, Shirley [1 ]
Ruppel, Kathleen M. [1 ]
Spudich, James A. [1 ,3 ]
机构
[1] Stanford Univ, Sch Med, Dept Biochem, Stanford, CA 94305 USA
[2] Inst Stem Cell Biol & Regenerat Med, Bangalore, Karnataka, India
[3] Stanford Univ, Sch Med, Dept Pediat Cardiol, Stanford, CA 94305 USA
关键词
BETA-CARDIAC MYOSIN; MUSCLE THICK FILAMENTS; LIGHT-CHAIN PHOSPHORYLATION; RABBIT SKELETAL-MUSCLE; SUPER-RELAXED STATE; BINDING PROTEIN-C; CRYO-EM; TARANTULA MUSCLE; STRUCTURAL BASIS; ATOMIC MODEL;
D O I
10.1038/nsmb.3408
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Hypertrophic cardiomyopathy (HCM) is primarily caused by mutations in beta-cardiac myosin and myosin-binding protein-C (MyBP-C). Changes in the contractile parameters of myosin measured so far do not explain the clinical hypercontractility caused by such mutations. We propose that hypercontractility is due to an increase in the number of myosin heads (S1) that are accessible for force production. In support of this hypothesis, we demonstrate myosin tail (S2)-dependent functional regulation of actin-activated human beta-cardiac myosin ATPase. In addition, we show that both S2 and MyBP-C bind to S1 and that phosphorylation of either S1 or MyBP-C weakens these interactions. Importantly, the S1-S2 interaction is also weakened by four myosin HCM-causing mutations but not by two other mutations. To explain these experimental results, we propose a working structural model involving multiple interactions, including those with myosin's own S2 and MyBP-C, that hold myosin in a sequestered state.
引用
收藏
页码:525 / +
页数:11
相关论文
共 82 条
[1]   Early-Onset Hypertrophic Cardiomyopathy Mutations Significantly Increase the Velocity, Force, and Actin-Activated ATPase Activity of Human β-Cardiac Myosin [J].
Adhikari, Arjun S. ;
Kooiker, Kristina B. ;
Sarkar, Saswata S. ;
Liu, Chao ;
Bernstein, Daniel ;
Spudich, James A. ;
Ruppel, Kathleen M. .
CELL REPORTS, 2016, 17 (11) :2857-2864
[2]   Atomic model of the human cardiac muscle myosin filament [J].
AL-Khayat, Hind A. ;
Kensler, Robert W. ;
Squire, John M. ;
Marston, Steven B. ;
Morris, Edward P. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2013, 110 (01) :318-323
[3]   Conserved Intramolecular Interactions Maintain Myosin Interacting-Heads Motifs Explaining Tarantula Muscle Super-Relaxed State Structural Basis [J].
Alamo, Lorenzo ;
Qi, Dan ;
Wriggers, Willy ;
Pinto, Antonio ;
Zhu, Jingui ;
Bilbao, Aivett ;
Gillilan, Richard E. ;
Hu, Songnian ;
Padron, Raul .
JOURNAL OF MOLECULAR BIOLOGY, 2016, 428 (06) :1142-1164
[4]   Three-Dimensional Reconstruction of Tarantula Myosin Filaments Suggests How Phosphorylation May Regulate Myosin Activity [J].
Alamo, Lorenzo ;
Wriggers, Willy ;
Pinto, Antonio ;
Bartoli, Fulvia ;
Salazar, Leiria ;
Zhao, Fa-Qing ;
Craig, Roger ;
Padron, Raul .
JOURNAL OF MOLECULAR BIOLOGY, 2008, 384 (04) :780-797
[5]   Genetic basis of hypertrophic cardiomyopathy: From bench to the clinics [J].
Alcalai, Ronny ;
Seidman, Jonathan G. ;
Seidman, Christine E. .
JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, 2008, 19 (01) :104-110
[6]   Update on activities at the Universal Protein Resource (UniProt) in 2013 [J].
Apweiler, Rolf ;
Martin, Maria Jesus ;
O'Donovan, Claire ;
Magrane, Michele ;
Alam-Faruque, Yasmin ;
Alpi, Emanuela ;
Antunes, Ricardo ;
Arganiska, Joanna ;
Casanova, Elisabet Barrera ;
Bely, Benoit ;
Bingley, Mark ;
Bonilla, Carlos ;
Britto, Ramona ;
Bursteinas, Borisas ;
Chan, Wei Mun ;
Chavali, Gayatri ;
Cibrian-Uhalte, Elena ;
Da Silva, Alan ;
De Giorgi, Maurizio ;
Dimmer, Emily ;
Fazzini, Francesco ;
Gane, Paul ;
Fedotov, Alexander ;
Castro, Leyla Garcia ;
Garmiri, Penelope ;
Hatton-Ellis, Emma ;
Hieta, Reija ;
Huntley, Rachael ;
Jacobsen, Julius ;
Jones, Rachel ;
Legge, Duncan ;
Liu, Wudong ;
Luo, Jie ;
MacDougall, Alistair ;
Mutowo, Prudence ;
Nightingale, Andrew ;
Orchard, Sandra ;
Patient, Samuel ;
Pichler, Klemens ;
Poggioli, Diego ;
Pundir, Sangya ;
Pureza, Luis ;
Qi, Guoying ;
Rosanoff, Steven ;
Sawford, Tony ;
Sehra, Harminder ;
Turner, Edward ;
Volynkin, Vladimir ;
Wardell, Tony ;
Watkins, Xavier .
NUCLEIC ACIDS RESEARCH, 2013, 41 (D1) :D43-D47
[7]   How cryo-EM is revolutionizing structural biology [J].
Bai, Xiao-Chen ;
McMullan, Greg ;
Scheres, Sjors H. W. .
TRENDS IN BIOCHEMICAL SCIENCES, 2015, 40 (01) :49-57
[8]   Structure of the Rigor Actin-Tropomyosin-Myosin Complex [J].
Behrmann, Elmar ;
Mueller, Mirco ;
Penczek, Pawel A. ;
Mannherz, Hans Georg ;
Manstein, Dietmar J. ;
Raunser, Stefan .
CELL, 2012, 150 (02) :327-338
[9]   Crystal structures of human cardiac β-myosin IIS2-Δ provide insight into the functional role of the S2 subfragment [J].
Blankenfeldt, Wulf ;
Thoma, Nicolas H. ;
Wray, John S. ;
Gautel, Mathias ;
Schlichting, Ilme .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (47) :17713-17717
[10]   A Molecular Model of Phosphorylation-Based Activation and Potentiation of Tarantula Muscle Thick Filaments [J].
Brito, Reicy ;
Alamo, Lorenzo ;
Lundberg, Ulf ;
Guerrero, Jose R. ;
Pinto, Antonio ;
Sulbaran, Guidenn ;
Gawinowicz, Mary Ann ;
Craig, Roger ;
Padron, Raul .
JOURNAL OF MOLECULAR BIOLOGY, 2011, 414 (01) :44-61