Disease relevance of Mhc

• Characterization of a hypercontraction-induced myopathy in Drosophila caused by mutations in Mhc [1].
• Susceptibility to insulin-dependent diabetes mellitus is linked to MHC class II genes [2].

Psychiatry related information on Mhc

• In vertebrate myosin I isoforms, the light chain is calmodulin, which is thought to regulate motor activity [3].

High impact information on Mhc

• Myosin motor proteins use the energy derived from ATP hydrolysis to move cargo along actin tracks [4].
• The role of actin isoforms has received little attention, largely because of the lack of a suitable cell type in which the myosin isoform remains constant yet the actin isoforms vary [5].
• How this myosin might orient the left-right axis has began to be elucidated by showing that it interacts directly with beta-catenin, suggesting that myosin ID interacts with the adherens junction to control the direction of organ looping [6].
• This is the first demonstration of a role of a myosin in body patterning [6].
• The identification of multiple isoforms of nonmuscle myosin-II, whose activities and regulation differ from that of smooth muscle myosin-II, suggests that, in addition to regulatory light chain phosphorylation, other regulatory mechanisms control vertebrate nonmuscle myosin-II activity [7].

Biological context of Mhc

• These mutants are caused by single point mutations in the ATP binding/hydrolysis domain of Mhc and lead to degeneration of the flight muscles [1].
• We show in this paper that neither sarcomeric myosin nor actin are required for myoblast fusion or the subsequent morphogenesis of muscle fibres, i.e. fibre morphogenesis does not depend on myofibrillogenesis [8].
• A portion of the Drosophila melanogaster MHC hinge is encoded by mutually exclusive alternative exons 15a and 15b, the use of which correlates with fast (hinge A) or slow (hinge B) muscle physiological properties [9].
• The GFP-tagged Myosin V1 rescued the male sterile phenotype of Jaguar showing it is functional in vivo [10].
• Comparison of the minimal promoter to Mhc genes of 10 Drosophila species identified putative regulatory elements in the upstream region and in the first intron [11].

Anatomical context of Mhc

• These embryos exhibit a dramatic absence of myosin heavy chain (MHC)-expressing myoblasts and lack differentiated muscle fibers [12].
• The molecular weight of the cytoplasmic myosin's light chains and peptide mapping and immunochemical analysis of its heavy chains demonstrate that this myosin, purified from Drosophila cell lines, is distinct from Drosophila muscle myosin [13].
• Polyclonal antiserum raised and reacted against Drosophila myosin isolated from cell lines cross-reacts only weakly with Drosophila muscle myosin isolated from the thoraces of adult Drosophila [13].
• Alternative s2 hinge regions of the Myosin rod differentially affect muscle function, myofibril dimensions and Myosin tail length [9].
• The altered transcriptional profile of dystrophic Mhc muscles suggests an actin-dependent remodeling of the muscle cytoskeleton [14].

Associations of Mhc with chemical compounds

• However, the NH2-terminal 12 residues show similarity to the NH2-terminal sequence of actin, a region that interacts with myosin [15].
• The myosin heavy and light chain genes, the actin genes, the troponin genes, and the atrial natriuretic factor and muscle creatine kinase genes have served as excellent paradigms for the study of cardiac gene expression [16].
• A clone of a fast isoform of myosin heavy chain (HC) gene was isolated from a cDNA1 expression library made from mRNA purified from the deep abdominal flexor muscle of the lobster, Homarus americanus [17].
• Aroclor 1254 and Cu(II) upregulated putative isoforms of tropomyosin and light chain of myosin [18].

Physical interactions of Mhc

• Here, two different solid-state binding assays demonstrate that flightin binds to myosin and to a recombinant fragment of the myosin rod that include the COOH-terminal 600 amino acids (zone 19 to tail piece) [19].
• Electron microscopy of isolated thick filaments and of myosin molecules suggests that the molecules are flexible, but myosin fragments and crossbridges have been reported not to interact with inappropriately oriented actin filaments [20].
• We describe the properties of a hybrid protein comprising the full length of the Xenopus laevis calmodulin sequence, followed by a pentapeptide linker (GGGGS), and residues 3-26 of M13, the calmodulin binding region of skeletal muscle myosin light chain kinase [21].

Enzymatic interactions of Mhc

• The mutations are associated with age-dependent, site-specific degradation of myosin heavy chain and failure to accumulate phosphorylated forms of flightin, an indirect flight muscle-specific protein previously localized to the thick filament [22].

Regulatory relationships of Mhc

• Mutations in the myosin heavy-chain gene that prevent thick filament assembly block accumulation of all flightin variants except N1, the unphosphorylated precursor, which is present at much reduced levels [23].
• In addition, we identified previously uncharacterized proteins with putative actin-interaction domains that are up-regulated in Mhc mutants and differentially expressed in muscles [14].
• Specific myosin heavy chain mutations suppress troponin I defects in Drosophila muscles [24].
• Exchanging the flight muscle-specific exon 3 region into the embryonic isoform increased actin sliding velocity 3-fold and improved indirect flight muscle ultrastructure integrity but failed to rescue the flightless phenotype of flies expressing embryonic myosin [25].

Other interactions of Mhc

• Characterization of these new Mhc alleles suggests that hypercontraction occurs via a mechanism, which is molecularly distinct from mutants identified previously in troponin I and troponin T [1].
• Previously, we exchanged two versions of this region (encoded by alternative exon 7s) between the indirect flight muscle myosin isoform (IFI) and an embryonic myosin isoform (EMB) and found, surprisingly, that in vitro solution actin-activated ATPase rates were increased (higher Vmax) by both exon exchanges [26].
• In intact muscles flightin is associated with the A band of the sarcomere, where evidence suggests it interacts with the myosin filaments [15].
• The nonmuscle myosin II heavy chain (MHC encoded by zipper is required for cell sheet movements in Drosophila embryos [27].
• Decoration of the thin filaments with myosin subfragment-1 in rigor conditions appeared not to be affected by the troponin [28].

Analytical, diagnostic and therapeutic context of Mhc

• To characterize the genomic response to hypercontraction-induced myopathy, we performed expression analysis using Affymetrix high density oligonucleotide microarrays in Drosophila Mhc hypercontraction alleles [14].
• Genomic and cDNA sequence analyses revealed that this 21-kilobase MHC gene encodes these MHC isoforms in 19 exons [29].
• Similarly, in Drosophila, actin and myosin 2 localization and cell constriction at the margin of the epidermis mediate dorsal closure and are controlled by Misshapen [30].
• Actin-myosin structures align across multiple cells during rosette formation, and adherens junction proteins assemble in a stepwise fashion during rosette resolution [31].
• Using a combination of molecular and genetic techniques we demonstrate that Ifm(2)2 is an allele of the single-copy sarcomeric myosin heavy chain gene [32].

References