A 29 residue region of the sarcomeric myosin rod is necessary for filament formation 1 1Edited by J. Karn

Sohn, Regina Lee; Vikstrom, Karen L.; Strauß, Michael; Cohen, Carolyn; Szent‐Györgyi, Albert; Leinwand, Leslie A.

doi:10.1006/jmbi.1996.0790

Cited by 148 publications

(166 citation statements)

References 71 publications

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“…A single charge change in the C. elegans paramyosin rod disrupts thick filament assembly (12). The assembly competence domain, a small, relatively neutral region in the rod domain near the C terminus found in both paramyosin and myosin (19), is believed to help initiate thick filament assembly (20). To our knowledge, previous to the current work, no investigations had been performed on the role of the nonhelical N-terminal domain of paramyosin in thick filament assembly.…”

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confidence: 90%

Paramyosin phosphorylation site disruption affects indirect flight muscle stiffness and power generation in Drosophila melanogaster

Liu

Miller

Swank

et al. 2005

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

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The phosphoprotein paramyosin is a major structural component of invertebrate muscle thick filaments. To investigate the importance of paramyosin phosphorylation, we produced transgenic Drosophila melanogaster in which one, three, or four phosphorylatable serine residues in the N-terminal nonhelical domain were replaced by alanines. Depending on the residues mutated, transgenic lines were either unaffected or severely flight impaired. Flight-impaired strains had decreases in the most acidic paramyosin isoforms, with a corresponding increase in more basic isoforms. Surprisingly, ultrastructure of indirect flight muscle myofibrils was normal, indicating N-terminal phosphorylation is not important for myofibril assembly. However, mechanical studies of active indirect flight muscle fibers revealed that phosphorylation site mutations reduced elastic and viscous moduli by 21-59% and maximum power output by up to 42%. Significant reductions also occurred under relaxed and rigor conditions, indicating that the phosphorylation-dependent changes are independent of strong crossbridge attachment and likely arise from alterations in thick filament backbone properties. Further, normal crossbridge kinetics were observed, demonstrating that myosin motor function is unaffected in the mutants. We conclude that N-terminal phosphorylation of Drosophila paramyosin is essential for optimal force and oscillatory power transduction within the muscle fiber and is key to the high passive stiffness of asynchronous insect flight muscles. Phosphorylation may reinforce interactions between myosin rod domains, enhance thick filament connections to the central M-line of the sarcomere and͞or stabilize thick filament interactions with proteins that contribute to fiber stiffness.contraction ͉ thick filament ͉ sarcomere ͉ mechanics ͉ insect P aramyosin is a major structural component of thick filaments in invertebrate muscle. The paramyosin to myosin ratio, which positively correlates with thick filament length and maximum active tension development (1), varies widely between different invertebrate phyla and even between different muscles within the same animal (2-5). For instance, this ratio is 1:34 in the fibrillar flight muscle of Drosophila melanogaster but is 1:6 in larval muscles (5). Sequence analysis of paramyosin isoforms isolated from different species reveal a rod-like molecule with a central ␣-helical region and two nonhelical terminal domains that can dimerize into a coiled-coil structure (6, 7). Like the myosin tail, amino acids of the paramyosin helical region have a periodic 28-residue positive and negative charge repeat distribution (6,8). This charge arrangement on the surfaces of paramyosin and the myosin tail may regulate the packing of these two proteins in the thick filament (6, 9, 10).Paramyosin is important for thick filament formation and for filament assembly into myofibrils (11,12). A currently accepted model of invertebrate thick filament assembly is that paramyosin molecules, together with other thick filament structur...

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confidence: 90%

Paramyosin phosphorylation site disruption affects indirect flight muscle stiffness and power generation in Drosophila melanogaster

Liu

Miller

Swank

et al. 2005

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

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“…9,10 Multimerization of CBFb-SMMHC and inhibition of AML1 activities depend upon the integrity of the evolutionarily conserved, 28-residue ACD. 11,12 CBFb-SMMHC inhibits proliferation of the 32Dcl3 myeloid and Ba/F3 lymphoid cell lines, dependent upon interaction with AML1 and integrity of the ACD. 6,7,12 Inhibition of proliferation is an unexpected phenotype for an oncoprotein, and the role of CBF and CBFb-SMMHC in regulating the proliferation of normal, primary marrow progenitor cells has not been well characterized.…”

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confidence: 99%

CBFβ-SMMHC slows proliferation of primary murine and human myeloid progenitors

et al. 2005

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CBFb-SMMHC is expressed in 8% of acute myeloid leukemias and inhibits AML1/RUNX1. In this study, murine marrow or human CD34 þ cells were transduced with retroviral or lentiviral vectors expressing CBFb-SMMHC or two mutant variants. CBFb-SMMHC reduced murine or human myeloid cell proliferation three-to four-fold in liquid culture relative to empty vectortransduced cells, during a period when vector-transduced cells accumulated five-fold and human cells 20-fold. CBFb-SMMHC decreased the formation of myeloid, but not erythroid, colonies two-to four-fold, and myeloid colonies expressing CBFb-SMMHC were markedly reduced in size. However, CBFb-SMMHC did not slow differentiation to granulocytes or monocytes. Neither CBFb-SMMHC(D2-11), which does not bind AML1, nor CBFb-SMMHC(DACD), which does not multimerize or efficiently bind corepressors, slowed proliferation or reduced myeloid colonies. CBFb-SMMHC increased the G1/S ratio 1.4-fold. AML1 had an effect opposite to CBFb-SMMHC, stimulating proliferation of murine myeloid progenitors 2.0-fold in liquid culture. Thus, CBFb-SMMHC directly inhibits the proliferation of normal myeloid progenitors via inhibition of AML1 and dependent upon the integrity of its assembly competence domain. These findings support the development of therapeutics that target the ability of CBFb-SMMHC to interact with AML1 or to multimerize via its assembly competence domain.

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“…It is the interaction of these charged repeats, in proper register, which is responsible for formation of the thick filament. Also crucial to the association of the rods is a region of 29 aa known as the assembly competent domain (ACD), which our laboratory has demonstrated to be necessary for the formation of myosin rod assemblies in vitro (11) .…”

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Mutations in the β-myosin rod cause myosin storage myopathy via multiple mechanisms

Armel

Leinwand

2009

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

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Myosin storage myopathy (MSM) is a congenital myopathy characterized by the presence of subsarcolemmal inclusions of myosin in the majority of type I muscle fibers, and has been linked to 4 mutations in the slow/cardiac muscle myosin, ␤-MyHC (MYH7). Although the majority of the >230 disease causing mutations in MYH7 are located in the globular head region of the molecule, those responsible for MSM are part of a subset of MYH7 mutations that are located in the ␣-helical coiled-coil tail. Mutations in the myosin head are thought to affect the ATPase and actin-binding properties of the molecule. To date, however, there are no reports of the molecular mechanism of pathogenesis for mutations in the rod region of muscle myosins. Here, we present analysis of 4 mutations responsible for MSM: L1793P, R1845W, E1886K, and H1901L. We show that each MSM mutation has a different molecular phenotype, suggesting that there are multiple mechanisms by which MSM can be caused. These mechanisms range from thermodynamic and functional irregularities of individual proteins (L1793P), to varying defects in the assembly and stability of filaments formed from the proteins (R1845W, E1886K, and H1901L). In addition to furthering our understanding of MSM, these observations provide the first insight into how mutations affect the rod region of muscle myosins, and provide a framework for future studies of disease-causing mutations in this region of the molecule.

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A 29 residue region of the sarcomeric myosin rod is necessary for filament formation 1 1Edited by J. Karn

Cited by 148 publications

References 71 publications

Paramyosin phosphorylation site disruption affects indirect flight muscle stiffness and power generation in Drosophila melanogaster

Paramyosin phosphorylation site disruption affects indirect flight muscle stiffness and power generation in Drosophila melanogaster

CBFβ-SMMHC slows proliferation of primary murine and human myeloid progenitors

Mutations in the β-myosin rod cause myosin storage myopathy via multiple mechanisms

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