"Z"eroing in on the role of Cypher in striated muscle function, signaling, and human disease.
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The striated muscle Z line, a multiprotein complex at the boundary between sarcomeres, plays an integral role in maintaining striated muscle structure and function. Multiple Z-line-associated proteins have been identified and shown to play an increasingly important role in the pathogenesis of human muscle disease. Cypher/Z-band alternatively spliced PDZ-motif protein, a PDZ-LIM protein in the Z line, binds to alpha-actinin (via its PDZ domain) and has been suggested to function as a linker-strut to maintain cytoskeletal structural integrity during contraction. Cypher may also participate in signaling pathways by binding to protein kinase C via its LIM domains. Analysis of Cypher-deficient mice has revealed that Cypher plays an integral role in Z-line maintenance/integrity of striated muscles and the pathogenesis of congenital myopathies, including cardiomyopathy. These studies have led to the subsequent discovery of Cypher mutations in human patients with dilated cardiomyopathy, hypertrophic cardiomyopathy, as well as skeletal muscle myopathies, which have been recently termed zaspopathies. The recent discovery of various alternatively spliced isoforms of Cypher with potentially distinct structural and signaling roles brings a different level of complexity to the mechanisms underlying Cypher-based human myopathies. This review will focus on recent developments on the role of Cypher and its isoforms in striated muscle structure, signaling, and disease to provide insights into the mechanisms involved in the pathogenesis of Z-line-associated human myopathies. (+info)
SALS, a WH2-domain-containing protein, promotes sarcomeric actin filament elongation from pointed ends during Drosophila muscle growth.
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Organization of actin filaments into a well-organized sarcomere structure is critical for muscle development and function. However, it is not completely understood how sarcomeric actin/thin filaments attain their stereotyped lengths. In an RNAi screen in Drosophila primary muscle cells, we identified a gene, sarcomere length short (sals), which encodes an actin-binding, WH2 domain-containing protein, required for proper sarcomere size. When sals is knocked down by RNAi, primary muscles display thin myofibrils with shortened sarcomeres and increased sarcomere number. Both loss- and gain-of-function analyses indicate that SALS may influence sarcomere lengths by promoting thin-filament lengthening from pointed ends. Furthermore, the complex localization of SALS and other sarcomeric proteins in myofibrils reveals that the full length of thin filaments is achieved in a two-step process, and that SALS is required for the second elongation phase, most likely because it antagonizes the pointed-end capping protein Tropomodulin. (+info)
An unstable head-rod junction may promote folding into the compact off-state conformation of regulated myosins.
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The N-terminal region of myosin's rod-like subfragment 2 (S2) joins the two heads of this dimeric molecule and is key to its function. Previously, a crystal structure of this predominantly coiled-coil region was determined for a short fragment (51 residues plus a leucine zipper) of the scallop striated muscle myosin isoform. In that study, the N-terminal 10-14 residues were found to be disordered. We have now determined the structure of the same scallop peptide in three additional crystal environments. In each of two of these structures, improved order has allowed visualization of the entire N-terminus in one chain of the dimeric peptide. We have also compared the melting temperatures of this scallop S2 peptide with those of analogous peptides from three other isoforms. Taken together, these experiments, along with examination of sequences, point to a diminished stability of the N-terminal region of S2 in regulated myosins, compared with those myosins whose regulation is thin filament linked. It seems plain that this isoform-specific instability promotes the off-state conformation of the heads in regulated myosins. We also discuss how myosin isoforms with varied thermal stabilities share the basic capacity to transmit force efficiently in order to produce contraction in their on states. (+info)
Cooperative control of striated muscle mass and metabolism by MuRF1 and MuRF2.
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The muscle-specific RING finger proteins MuRF1 and MuRF2 have been proposed to regulate protein degradation and gene expression in muscle tissues. We have tested the in vivo roles of MuRF1 and MuRF2 for muscle metabolism by using knockout (KO) mouse models. Single MuRF1 and MuRF2 KO mice are healthy and have normal muscles. Double knockout (dKO) mice obtained by the inactivation of all four MuRF1 and MuRF2 alleles developed extreme cardiac and milder skeletal muscle hypertrophy. Muscle hypertrophy in dKO mice was maintained throughout the murine life span and was associated with chronically activated muscle protein synthesis. During ageing (months 4-18), skeletal muscle mass remained stable, whereas body fat content did not increase in dKO mice as compared with wild-type controls. Other catabolic factors such as MAFbox/atrogin1 were expressed at normal levels and did not respond to or prevent muscle hypertrophy in dKO mice. Thus, combined inhibition of MuRF1/MuRF2 could provide a potent strategy to stimulate striated muscles anabolically and to protect muscles from sarcopenia during ageing. (+info)
Zasp is required for the assembly of functional integrin adhesion sites.
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