Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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A monoclonal antibody, MF20, which has been shown previously to bind the myosin heavy chain of vertebrate striated muscle, has been proven to bind the light meromyosin (LMM) fragment by solid phase radioimmune assay with alpha-chymotryptic digests of purified myosin. Epitope mapping by electron microscopy of rotary-shadowed, myosin-antibody complexes has localized the antibody binding site to LMM at a point approximately 92 nm from the C-terminus of the myosin heavy chain. Since this epitope in native thick filaments is accessible to monoclonal antibodies, we used this antibody as a high affinity ligand to analyze the packing of LMM along the backbone of the thick filament. By immunofluorescence microscopy, MF20 was shown to bind along the entire A-band of chicken pectoralis myofibrils, although the epitope accessibility was greater near the ends than at the center of the A-bands. Thin-section, transmission electron microscopy of myofibrils decorated with MF20 revealed 50 regularly spaced, cross-striations in each half A-band, with a repeat distance of approximately 13 nm. These were numbered consecutively, 1-50, from the A-band to the last stripe, approximately 68 nm from the filament tips. These same striations could be visualized by negative staining of native thick filaments labeled with MF20. All 50 striations were of a consecutive, uninterrupted repeat which approximated the 14-15-nm axial translation of cross-bridges. Each half M-region contained five MF20 striations (approximately 13 nm apart) with a distance between stripes 1 and 1', on each half of the bare zone, of approximately 18 nm. This is compatible with a packing model with full, antiparallel overlap of the myosin rods in the bare zone region. Differences in the spacings measured with negatively stained myofilaments and thin-sectioned myofibrils have been shown to arise from specimen shrinkage in the fixed and embedded preparations. These observations provide strong support for Huxley's original proposal for myosin packing in thick filaments of vertebrate muscle (Huxley, H. E., 1963, J. Mol. Biol., 7:281-308) and, for the first time, directly demonstrate that the 14-15-nm axial translation of LMM in the thick filament backbone corresponds to the cross-bridge repeat detected with x-ray diffraction of living muscle.
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PMID:Axial arrangement of the myosin rod in vertebrate thick filaments: immunoelectron microscopy with a monoclonal antibody to light meromyosin. 389 43

The mutation e1662 is an allele of the Caenorhabditis elegans unc-54 gene induced with the difunctional alkylating agent 1,2,7,8-diepoxyoctane. unc-54 encodes the major myosin heavy chain isozyme of body wall muscle cells. Filter-transfer hybridization and DNA sequence analysis show that e1662 is an insertion of 288 base pairs of DNA within unc-54. The inserted DNA is identical to a 288-base pair region of unc-54 located ca. 600 base pairs from the insertion site. Thus, e1662 is a displaced duplication. A 14-base pair sequence located at one end of the duplicated segment is found adjacent to the site of insertion. These homologous sequences are juxtaposed head-to-tail by the insertion event. e1662 thus contains a tandem direct repeat extending across one of its junctions.
Mol Cell Biol 1985 Jan
PMID:Novel insertion mutation in Caenorhabditis elegans. 398 11

We have sequenced 11 representative mutations of the unc-54 myosin heavy chain gene of Caenorhabditis elegans that affect the synthesis, assembly or enzymatic activity of the encoded myosin heavy chain. Six of the sequenced unc-54 mutations cause premature termination of protein synthesis. Four mutations (e1092, e1115, e1213, e1328) were ochre mutations, one mutation (e903) was a frameshift, which caused premature termination at a nearby UGA terminator, and one mutation (e190) was a deletion that altered the reading frame and caused termination at an ochre codon. Two mutations (e675 and s291) were inphase deletions, which resulted in a shortened myosin rod segment. These aberrant myosins fail to assemble into normal thick filaments. The sequence alterations of the missense mutations (e1152, s74, s95) indicated amino acid residues that are critical for myosin function. The mutation e1152 causes the production of a myosin heavy chain that fails to assemble into thick filaments. It had two adjacent amino acid substitutions at the extreme amino terminus of the rod, indicating a role for subfragment-2 in thick filament assembly. Mutants homozygous for s74 or s95 are very slow-moving, although they make myosin heavy chains that assemble normally. The encoded amino acid substitutions of s95 and s74 are in the 23 X 10(3) Mr and 50 X 10(3) Mr domains of the myosin head, flanking the ATP binding site. The sequenced mutations are distributed throughout the gene in the order predicted from genetic fine-structure mapping experiments. Seven of eight point mutations isolated following ethylmethane sulphonate mutagenesis were G X C to A X T transitions. A single X-ray-induced allele proved to be a deletion of two adjacent thymidine residues. The three deletion mutations were found in a region of the myosin rod with numerous direct and inverted nucleotide sequence repeats, but their origin cannot be accounted for by homologous recombination. Instead, a comparison of the deletion junctions suggests that the deletions arose by a site-specific mechanism.
J Mol Biol 1985 Jun 25
PMID:Sequence analysis of mutations that affect the synthesis, assembly and enzymatic activity of the unc-54 myosin heavy chain of Caenorhabditis elegans. 402 Aug 69

Since systemic actions of thyroid hormone increase cardiac work, direct effects of T3 on myocardial protein turnover may be obscured in the intact animal. For this reason, the effects of T3 on synthesis and degradation of cellular protein were measured in replicate cultures of cardiac myocytes obtained from chick embryos. During the first 3 days of exposure, 10(-8) M T3 increased the fractional rate of protein synthesis 10% to 16% and the fractional rate of cell growth 20% to 40% with no change in protein degradation. During the fourth and fifth days of 10(-8) M T3 exposure, fractional synthesis rates in T3 cultures increased 15% to 19% but fractional degradation rates also increased 17% to 29% so that growth rates in T3 cultures fell to control levels. Similar changes in myocardial protein turnover have occurred in response to T3 treatment in intact animals. T3 treatment caused a disproportionately large increase in the rate of myosin heavy chain turnover when compared to total cellular protein and actin. This may be related to the change in amounts of myocardial isomyosins occurring in response to thyroid hormone treatment.
J Mol Cell Cardiol 1985 Sep
PMID:Effect of thyroid hormone on protein turnover in cultured cardiac myocytes. 404 50

We have cloned and sequenced a complementary DNA copy (pSS48) of a novel muscle-specific, low molecular weight RNA, 7 S RNA, isolated from embryonic chick cardiac muscle cells. The hybridization pattern of plasmid pSS48 DNA to chick genomic DNA suggests that 7 S RNA is derived from the repetitive chick DNA with a repetition frequency of about 300 copies per haploid genome. Under low stringency, pSS48 DNA also hybridizes with high specificity to the single copy gene for chick myosin light chain (MLC) and to myosin heavy chain (MHC), and possibly to other co-ordinately expressed genes for chick muscle proteins. The sequence analysis of recombinant plasmids pSS48, pML10 and pMHC8, for 7 S RNA, MLC mRNA and MHC RNA, respectively, indicated that short nucleotide stretches homologous to 7 S RNA reside in the 3' untranslated regions of the respective genes. The 7 S RNA sequence appears to be highly specific for the chick muscle tissue, since RNA and DNA from several sources did not hybridize to pSS48 DNA. Furthermore, the 7 S RNA-like sequence(s) appears in chick blastodermal cells preferentially earlier than the onset of transcription of genes for major muscle proteins. These results, taken together, suggest a possible function for 7 S RNA in expression of muscle-specific genes during chick development.
J Mol Biol 1984 Dec 15
PMID:Co-ordinate control of gene expression. Muscle-specific 7 S RNA contains sequences homologous to 3'-untranslated regions of myosin genes and repetitive DNA. 608 16

It has been recognized for a long time that changes in hormone secretion can influence cardiac function; however, the biochemical basis for these changes has only recently been clarified. In this review the influences of hormonal status on the contractile protein myosin is discussed. Myosin has a rod-like portion and a globular head and consists of two myosin heavy chains (MHC) and four light chains (LC), two of which are identical. The globular head is the site of an ATP-splitting enzyme, the myosin ATPase, and increases in myosin ATPase activity are closely related to an increased velocity of contraction of the heart. Myosin ATPase activity shows marked response to alterations in thyroid hormone, insulin, glucocorticoid, testosterone and catecholamine levels, but marked animal species differences in this response occur. Thyroid hormone administration to normal rabbits, for example, increases myosin ATPase activity markedly, but the myosin ATPase activity of hyperthyroid rats remains unchanged. In contrast, in hypothyroid rats myosin ATPase activity is markedly decreased but the hypothyroid rabbit shows no such response. These species-related differences in the hormonal response of myosin ATPase activity result from the predominance pattern of specific myosin isoenzymes. In the normal rat heart three myosin isoenzymes, V1, V2 and V3, can be separated electrophoretically. Myosin V1 predominates (70% of total myosin), and has the highest myosin ATPase activity, whereas in rabbits myosin V3, which has a lower myosin ATPase activity, is the predominant isomyosin. Thyroid hormone administration to rabbits induces myosin V1 predominance and therefore increases myosin ATPase activity, whereas in hyperthyroid rats only a small further increase in V1 predominance can occur. The alterations in myosin isoenzyme predominance and myosin ATPase activity are closely correlated to changes in cardiac contractility. Hormone-induced alterations in myosin isoenzyme predominance are mediated through changes in the formation of two isoforms of myosin heavy chain. Changes in the expression of different myosin heavy chain genes are most likely responsible for the thyroid hormone and insulin-induced alterations in myosin isoenzyme predominance. Investigation of the control of myosin heavy chain formation can provide further insights into the hormonal control of a multigene family as well as broaden our understanding of the molecular events which result in altered cardiac contractility.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Cell Endocrinol 1984 Mar
PMID:Hormonal influences on cardiac myosin ATPase activity and myosin isoenzyme distribution. 623 63

Light meromyosin (LMM), prepared by limited tryptic digestion of myosin, usually contains several polypeptide chains, LMM-A, LMM-B, and LMM-C in decreasing order of molecular weight estimated from sodium dodecyl sulfate-gel electrophoresis. Further limited tryptic digestion of LMM produces well defined fragments (Balint, M., Szilagyi, L., Fekete, Gy., Blazso, M., and Biro, E. N. A. J. Mol. Biol. (1968) 37, 317-330). Fragments LF-1, LMM-D, LF-2, and LF-3, with chain masses equal to 63, 56, 47, and 30 kDa, respectively, have been isolated by column chromatography. Based on the time course of the changes in the sodium dodecyl sulfate-gel pattern of the digests, chain masses estimated from sodium dodecyl sulfate-gel electrophoresis, and the NH2- and COOH-terminal sequences of the isolated peptides, the following scheme can be deduced. Formula; see text. C and N over the arrows indicate removal of residues from the COOH and NH2 terminus, respectively. The positions of the peptides along the myosin heavy chain have been established by comparison with the published primary structures of rabbit skeletal (Elzinga, M., Behar, K., Walton, G., and Trus, B. L. (1980) Fed. Proc. 33, 1579) and nematode myosin (McLachlan, A. D., and Karn, J. (1982) Nature (Lond.) 299, 226-231). LMM and fragment LMM-D are insoluble, whereas LF-1, LF-2, and LF-3 are soluble at low ionic strength. Their solubility properties, in conjunction with their locations along the myosin heavy chain, suggest that a relatively small stretch of peptide (chain weight, 5,000 Da) located about 100 residues from the COOH terminus of myosin heavy chain is responsible for the insolubility of LMM at low ionic strength.
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PMID:The proteolytic substructure of light meromyosin. Localization of a region responsible for the low ionic strength insolubility of myosin. 635 7

Densitometric scanning of SDS-polyacrylamide gels was used to measure myosin heavy chain concentration in left ventricular specimens obtained from cat hearts 3 to 12 months after healing of small experimental myocardial infarctions. The study was designed to test the hypothesis that myosin concentration varies as a function of anatomic proximity to the infarct scar. Myosin heavy chain concentration was elevated in non-scarred areas adjacent to a healed infarct and normal in areas remote from the scar. The scar itself had reduced concentrations, reflecting the loss of muscle mass in this area. The increased myosin heavy chain concentration in regions adjacent to the scar may be an attempt to regulate or compensate for the decrease in mechanical function of the scarred area.
J Mol Cell Cardiol 1984 Jun
PMID:Regional variations in myosin heavy chain concentration after healing of experimental myocardial infarction in cats. 674 90

Rat cardiac ventricular myosins were obtained from fetuses, from young normal animals, and from hypophysectomized adults. The purified proteins were compared by several techniques: (i) electrophoresis in non-denaturing conditions (pyrophosphate buffer), (ii) one- and two-dimensional analysis after proteolytic cleavage, (iii) immunological blotting after electrophoretic purification, and (iv) competitive enzyme-linked immunosorbent assay. Antibodies specific to each of the two major isoenzymes of adult rat heart (V1 and V3 according to the terminology of Hoh et al. (Hoh, J. F. Y., McGrath, P. A., and Hale, P. T. (1978) J. Mol. Cell. Cardiol. 10, 1053-1076) were used for the immunological studies. The heavy chains of the ventricular myosin isoenzymes of fetuses (V3F) were indistinguishable from those of the V3H isoenzyme present in hypophysectomized adults; both proteins differed from the V1 isoform of young animals. The light chains of V3F, V3H, and V1 were the same, except that V3F contained in addition a small amount of the embryonic light chain (Whalen, R. G., and Sell, S. M. (1980) Nature 286, 731-733). These results strongly suggest that adaptation of the adult rat heart to the hormonal deficiencies of hypophysectomy is mediated by the synthesis of the same myosin heavy chain form which is predominant in fetal hearts.
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PMID:Comparisons of rat cardiac myosins at fetal stages in young animals and in hypothyroid adults. 714 19

The structures of the heavy chains of fast-twitch white muscle myosin isolated from a number of specific rabbit muscles were examined by the technique of tryptic peptide mapping of iodinated proteins from sodium dodecyl sulfate polyacrylamide gels. The results suggest that the distribution of the two closely related heavy chain isozymes postulated to exist by Starr and Offer ((1973) J. Mol. Biol. 81, 17-31) vary in a muscle-specific manner. One isozyme appears to be preferentially located in the extensor digitorum longus muscle, while the other appears to be preferentially located in the semitendinosus muscle. Other muscles, such as the gastrocnemius and the latissimus dorsi, appear to contain the two isozymes in a nearly 1:1 ratio. Fine structure mapping of myosin fragments revealed that the two muscle-specific isozymes differ in a number of locations throughout the head and tail portions of the myosin heavy chain.
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PMID:The muscle specificity and structure of two closely related fast-twitch white muscle myosin heavy chain isozymes. 729 34


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