Coiled-Coil Unwinding at the Smooth Muscle Myosin Head-Rod Junction Is Required for Optimal Mechanical Performance

Lauzon, Anne-Marie; Fagnant, Patty; Warshaw, David M.; Trybus, Kathleen M.

doi:10.1016/s0006-3495(01)76159-0

Cited by 41 publications

(19 citation statements)

References 24 publications

(31 reference statements)

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“…The observation of different structures of the N terminus of S2, ranging from disordered in scallop S2N51 (9) to partially ordered͞␣-helical (WT-S2-⌬) to coiled coil (E924K-S2-⌬), indi- cates that only a small energy barrier needs to be overcome to induce different structural states in the first dozen residues. This small barrier may help in reconciling previous studies that demonstrated the necessity for the presence of the labile native S2 sequence in generating a full powerstroke (14) but found uncoiling limited to only a small part of S2 in two-headed rigor binding to actin (3,15).…”

Section: Resultssupporting

confidence: 74%

Crystal structures of human cardiac β-myosin II S2-Δ provide insight into the functional role of the S2 subfragment

Blankenfeldt

Thomä

Wray

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

100

132

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Myosin II is the major component of the muscle thick filament. It consists of two N-terminal S1 subfragments (''heads'') connected to a long dimeric coiled-coil rod. The rod is in itself twofold symmetric, but in the filament, the two heads point away from the filament surface and are therefore not equivalent. This breaking of symmetry requires the initial section of the rod, subfragment 2 (S2), to be relatively flexible. S2 is an important functional element, involved in various mechanisms by which the activity of smooth and striated muscle is regulated. We have determined crystal structures of the 126 N-terminal residues of S2 from human cardiac ␤-myosin II (S2-⌬), of both WT and the disease-associated E924K mutant. S2-⌬ is a straight parallel dimeric coiled coil, but the N terminus of one chain is disordered in WT-S2-⌬ due to crystal contacts, indicative of unstable local structure. Bulky noncanonical side chains pack into a͞d positions of S2-⌬'s N terminus, leading to defined local asymmetry and axial stagger, which could induce nonequivalence of the S1 subfragments. Additionally, S2 possesses a conserved charge distribution with three prominent rings of negative potential within S2-⌬, the first of which may provide a binding interface for the ''blocked head'' of smooth muscle myosin in the OFF state. The observation that many disease-associated mutations affect the second negatively charged ring further suggests that charge interactions play an important role in regulation of cardiac muscle activity through myosin-binding protein C.coiled coil ͉ muscle ͉ crystallography ͉ regulation ͉ familial hypertrophic cardiomyopathy M uscle contraction results from the ATP-dependent cyclic interaction of the proteins myosin II and actin, assembled in thick and thin filaments, respectively. Myosin II consists of two heavy chains, each of which binds one essential and one regulatory light chain (Fig.

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Section: Resultssupporting

confidence: 74%

Crystal structures of human cardiac β-myosin II S2-Δ provide insight into the functional role of the S2 subfragment

Blankenfeldt

Thomä

Wray

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

100

132

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“…We were unable to find any satisfactory models with such a coiled rod conformation. Our model is consistent with the idea that optimal mechanical performance of SMM may require the rod to uncoil near the heads (39).…”

supporting

confidence: 87%

Structural Model of the Regulatory Domain of Smooth Muscle Heavy Meromyosin

Wahlstrom¹,

Randall²,

Lawson³

et al. 2003

Journal of Biological Chemistry

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The goal of this study was to provide structural information about the regulatory domains of double-headed smooth muscle heavy meromyosin, including the N terminus of the regulatory light chain, in both the phosphorylated and unphosphorylated states. We extended our previous photo-cross-linking studies (Wu, X., Clack, B. A., Zhi, G., Stull, J. T., and Cremo, C. R. Both cross-links were to the partner regulatory light chain and occurred in unphosphorylated but not phosphorylated heavy meromyosin. Using these data, data from our previous study, and atomic coordinates from various myosin isoforms, we have constructed a structural model of the regulatory domain in an unphosphorylated double-headed molecule that predicts the general location of the N terminus. The implications for the structural basis of the phosphorylation-mediated regulatory mechanism are discussed.

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“…34). Another explanation is that muscle myosin needs both heads to generate maximum force and motion (32) and that coordination of the heads requires the region of the coiled-coil rod near the S2-segment to unwind or breathe (12). It is possible that the L908V and the D906G mutations exert their effect through alterations to head-head interactions by virtue of their effect on S2-segment flexibility.…”

Section: Discussionmentioning

confidence: 99%

Molecular and phenotypic effects of heterozygous, homozygous, and compound heterozygote myosin heavy-chain mutations

Alpert¹,

Mohiddin²,

Tripodi³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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. Molecular and phenotypic effects of heterozygous, homozygous, and compound heterozygote myosin heavy-chain mutations. Am J Physiol Heart Circ Physiol 288: H1097-H1102, 2005. First published November 4, 2004 doi:10.1152/ajpheart.00650.2004.-Autosomal dominant familial hypertrophic cardiomyopathy (FHC) has variable penetrance and phenotype. Heterozygous mutations in MYH7 encoding ␤-myosin heavy chain are the most common causes of FHC, and we proposed that "enhanced" mutant actin-myosin function is the causative molecular abnormality. We have studied individuals from families in which members have two, one, or no mutant MYH7 alleles to examine for dose effects. In one family, a member homozygous for Lys207Gln had cardiomyopathy complicated by left ventricular dilatation, systolic impairment, atrial fibrillation, and defibrillator interventions. Only one of five heterozygous relatives had FHC. Leu908Val and Asp906Gly mutations were detected in a second family in which penetrance for Leu908Val heterozygotes was 46% (21/46) and 25% (3/12) for Asp906Gly. Despite the low penetrance, hypertrophy was severe in several heterozygotes. Two individuals with both mutations developed severe FHC. The velocities of actin translocation (V actin) by mutant and wild-type (WT) myosins were compared in the in vitro motility assay. Compared with WT/WT, V actin was 34% faster for WT/D906G and 21% for WT/L908V. Surprisingly V actin for Leu908Val/Asp906Gly and Lys207Gln/Lys207Gln mutants were similar to WT. The apparent enhancement of mechanical performance with mutant/WT myosin was not observed for mutant/mutant myosin. This suggests that V actin may be a poor predictor of disease penetrance or severity and that power production may be more appropriate, or that the limited availability of double mutant patients prohibits any definitive conclusions. Finally, severe FHC in heterozygous individuals can occur despite very low penetrance, suggesting these mutations alone are insufficient to cause FHC and that uncharacterized modifying mechanisms exert powerful influences.

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Coiled-Coil Unwinding at the Smooth Muscle Myosin Head-Rod Junction Is Required for Optimal Mechanical Performance

Cited by 41 publications

References 24 publications

Crystal structures of human cardiac β-myosin II S2-Δ provide insight into the functional role of the S2 subfragment

Crystal structures of human cardiac β-myosin II S2-Δ provide insight into the functional role of the S2 subfragment

Structural Model of the Regulatory Domain of Smooth Muscle Heavy Meromyosin

Molecular and phenotypic effects of heterozygous, homozygous, and compound heterozygote myosin heavy-chain mutations

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