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Proc Natl Acad Sci U S A. Apr 25, 1995; 92(9): 3864–3868.
PMCID: PMC42062

Structural interpretation of the mutations in the beta-cardiac myosin that have been implicated in familial hypertrophic cardiomyopathy.

Abstract

In 10-30% of hypertrophic cardiomyopathy kindreds, the disease is caused by > 29 missense mutations in the cardiac beta-myosin heavy chain (MYH7) gene. The amino acid sequence similarity between chicken skeletal muscle and human beta-cardiac myosin and the three-dimensional structure of the chicken skeletal muscle myosin head have provided the opportunity to examine the structural consequences of these naturally occurring mutations in human beta-cardiac myosin. This study demonstrates that the mutations are related to distinct structural and functional domains. Twenty-four are clustered around four specific locations in the myosin head that are (i) associated with the actin binding interface, (ii) around the nucleotide binding site, (iii) adjacent to the region that connects the two reactive cysteine residues, and (iv) in close proximity to the interface of the heavy chain with the essential light chain. The remaining five mutations are in the myosin rod. The locations of these mutations provide insight into the way they impair the functioning of this molecular motor and also into the mechanism of energy transduction.

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  • INGRAM VM. Gene mutations in human haemoglobin: the chemical difference between normal and sickle cell haemoglobin. Nature. 1957 Aug 17;180(4581):326–328. [PubMed]
  • Finch JT, Perutz MF, Bertles JF, Döbler J. Structure of sickled erythrocytes and of sickle-cell hemoglobin fibers. Proc Natl Acad Sci U S A. 1973 Mar;70(3):718–722. [PMC free article] [PubMed]
  • Epstein ND, Cohn GM, Cyran F, Fananapazir L. Differences in clinical expression of hypertrophic cardiomyopathy associated with two distinct mutations in the beta-myosin heavy chain gene. A 908Leu----Val mutation and a 403Arg----Gln mutation. Circulation. 1992 Aug;86(2):345–352. [PubMed]
  • Fananapazir L, Epstein ND. Genotype-phenotype correlations in hypertrophic cardiomyopathy. Insights provided by comparisons of kindreds with distinct and identical beta-myosin heavy chain gene mutations. Circulation. 1994 Jan;89(1):22–32. [PubMed]
  • Fananapazir L, Dalakas MC, Cyran F, Cohn G, Epstein ND. Missense mutations in the beta-myosin heavy-chain gene cause central core disease in hypertrophic cardiomyopathy. Proc Natl Acad Sci U S A. 1993 May 1;90(9):3993–3997. [PMC free article] [PubMed]
  • Watkins H, Rosenzweig A, Hwang DS, Levi T, McKenna W, Seidman CE, Seidman JG. Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy. N Engl J Med. 1992 Apr 23;326(17):1108–1114. [PubMed]
  • Geisterfer-Lowrance AA, Kass S, Tanigawa G, Vosberg HP, McKenna W, Seidman CE, Seidman JG. A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation. Cell. 1990 Sep 7;62(5):999–1006. [PubMed]
  • Harada H, Kimura A, Nishi H, Sasazuki T, Toshima H. A missense mutation of cardiac beta-myosin heavy chain gene linked to familial hypertrophic cardiomyopathy in affected Japanese families. Biochem Biophys Res Commun. 1993 Jul 30;194(2):791–798. [PubMed]
  • Consevage MW, Salada GC, Baylen BG, Ladda RL, Rogan PK. A new missense mutation, Arg719Gln, in the beta-cardiac heavy chain myosin gene of patients with familial hypertrophic cardiomyopathy. Hum Mol Genet. 1994 Jun;3(6):1025–1026. [PubMed]
  • Nishi H, Kimura A, Harada H, Toshima H, Sasazuki T. Novel missense mutation in cardiac beta myosin heavy chain gene found in a Japanese patient with hypertrophic cardiomyopathy. Biochem Biophys Res Commun. 1992 Oct 15;188(1):379–387. [PubMed]
  • Dausse E, Komajda M, Fetler L, Dubourg O, Dufour C, Carrier L, Wisnewsky C, Bercovici J, Hengstenberg C, al-Mahdawi S, et al. Familial hypertrophic cardiomyopathy. Microsatellite haplotyping and identification of a hot spot for mutations in the beta-myosin heavy chain gene. J Clin Invest. 1993 Dec;92(6):2807–2813. [PMC free article] [PubMed]
  • Watkins H, Thierfelder L, Hwang DS, McKenna W, Seidman JG, Seidman CE. Sporadic hypertrophic cardiomyopathy due to de novo myosin mutations. J Clin Invest. 1992 Nov;90(5):1666–1671. [PMC free article] [PubMed]
  • al-Mahdawi S, Chamberlain S, Cleland J, Nihoyannopoulos P, Gilligan D, French J, Choudhury L, Williamson R, Oakley C. Identification of a mutation in the beta cardiac myosin heavy chain gene in a family with hypertrophic cardiomyopathy. Br Heart J. 1993 Feb;69(2):136–141. [PMC free article] [PubMed]
  • Toyoshima YY, Kron SJ, McNally EM, Niebling KR, Toyoshima C, Spudich JA. Myosin subfragment-1 is sufficient to move actin filaments in vitro. Nature. 1987 Aug 6;328(6130):536–539. [PubMed]
  • Itakura S, Yamakawa H, Toyoshima YY, Ishijima A, Kojima T, Harada Y, Yanagida T, Wakabayashi T, Sutoh K. Force-generating domain of myosin motor. Biochem Biophys Res Commun. 1993 Nov 15;196(3):1504–1510. [PubMed]
  • Warrick HM, Spudich JA. Myosin structure and function in cell motility. Annu Rev Cell Biol. 1987;3:379–421. [PubMed]
  • Chothia C, Lesk AM. The relation between the divergence of sequence and structure in proteins. EMBO J. 1986 Apr;5(4):823–826. [PMC free article] [PubMed]
  • Rayment I, Rypniewski WR, Schmidt-Bäse K, Smith R, Tomchick DR, Benning MM, Winkelmann DA, Wesenberg G, Holden HM. Three-dimensional structure of myosin subfragment-1: a molecular motor. Science. 1993 Jul 2;261(5117):50–58. [PubMed]
  • Rayment I, Holden HM, Whittaker M, Yohn CB, Lorenz M, Holmes KC, Milligan RA. Structure of the actin-myosin complex and its implications for muscle contraction. Science. 1993 Jul 2;261(5117):58–65. [PubMed]
  • Devereux J, Haeberli P, Smithies O. A comprehensive set of sequence analysis programs for the VAX. Nucleic Acids Res. 1984 Jan 11;12(1 Pt 1):387–395. [PMC free article] [PubMed]
  • Maita T, Yajima E, Nagata S, Miyanishi T, Nakayama S, Matsuda G. The primary structure of skeletal muscle myosin heavy chain: IV. Sequence of the rod, and the complete 1,938-residue sequence of the heavy chain. J Biochem. 1991 Jul;110(1):75–87. [PubMed]
  • Jaenicke T, Diederich KW, Haas W, Schleich J, Lichter P, Pfordt M, Bach A, Vosberg HP. The complete sequence of the human beta-myosin heavy chain gene and a comparative analysis of its product. Genomics. 1990 Oct;8(2):194–206. [PubMed]
  • Cooke R. The mechanism of muscle contraction. CRC Crit Rev Biochem. 1986;21(1):53–118. [PubMed]
  • Bálint M, Sréter FA, Wolf I, Nagy B, Gergely J. The substructure of heavy meromyosin. The effect of Ca2+ and Mg2+ on the tryptic fragmentation of heavy meromyosin. J Biol Chem. 1975 Aug 10;250(15):6168–6177. [PubMed]
  • Mornet D, Pantel P, Audemard E, Kassab R. The limited tryptic cleavage of chymotryptic S-1: an approach to the characterization of the actin site in myosin heads. Biochem Biophys Res Commun. 1979 Aug 13;89(3):925–932. [PubMed]
  • Holmes KC, Popp D, Gebhard W, Kabsch W. Atomic model of the actin filament. Nature. 1990 Sep 6;347(6288):44–49. [PubMed]
  • Milligan RA, Whittaker M, Safer D. Molecular structure of F-actin and location of surface binding sites. Nature. 1990 Nov 15;348(6298):217–221. [PubMed]
  • Milligan RA, Flicker PF. Structural relationships of actin, myosin, and tropomyosin revealed by cryo-electron microscopy. J Cell Biol. 1987 Jul;105(1):29–39. [PMC free article] [PubMed]
  • Cuda G, Fananapazir L, Zhu WS, Sellers JR, Epstein ND. Skeletal muscle expression and abnormal function of beta-myosin in hypertrophic cardiomyopathy. J Clin Invest. 1993 Jun;91(6):2861–2865. [PMC free article] [PubMed]
  • Sweeney HL, Straceski AJ, Leinwand LA, Tikunov BA, Faust L. Heterologous expression of a cardiomyopathic myosin that is defective in its actin interaction. J Biol Chem. 1994 Jan 21;269(3):1603–1605. [PubMed]
  • Yount RG, Cremo CR, Grammer JC, Kerwin BA. Photochemical mapping of the active site of myosin. Philos Trans R Soc Lond B Biol Sci. 1992 Apr 29;336(1276):55–61. [PubMed]
  • Cheung HC, Gonsoulin F, Garland F. Fluorescence energy transfer studies on the proximity of the two essential thiols of myosin subfragment-1. J Biol Chem. 1983 May 10;258(9):5775–5786. [PubMed]
  • Dalbey RE, Weiel J, Yount RG. Förster energy transfer measurements of thiol 1 to thiol 2 distances in myosin subfragment 1. Biochemistry. 1983 Sep 27;22(20):4696–4706. [PubMed]
  • Huston EE, Grammer JC, Yount RG. Flexibility of the myosin heavy chain: direct evidence that the region containing SH1 and SH2 can move 10 A under the influence of nucleotide binding. Biochemistry. 1988 Dec 13;27(25):8945–8952. [PubMed]
  • Botts J, Thomason JF, Morales MF. On the origin and transmission of force in actomyosin subfragment 1. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2204–2208. [PMC free article] [PubMed]
  • Reisler E, Burke M, Himmelfarb S, Harrington WF. Spatial proximity of the two essential sulfhydryl groups of myosin. Biochemistry. 1974 Sep 10;13(19):3837–3840. [PubMed]
  • Burke M, Reisler E. Effect of nucleotide binding on the proximity of the essential sulfhydryl groups of myosin. Chemical probing of movement of residues during conformational transitions. Biochemistry. 1977 Dec 13;16(25):5559–5563. [PubMed]
  • Wells JA, Yount RG. Active site trapping of nucleotides by crosslinking two sulfhydryls in myosin subfragment 1. Proc Natl Acad Sci U S A. 1979 Oct;76(10):4966–4970. [PMC free article] [PubMed]
  • Rayment I, Holden HM. The three-dimensional structure of a molecular motor. Trends Biochem Sci. 1994 Mar;19(3):129–134. [PubMed]
  • Kishino A, Yanagida T. Force measurements by micromanipulation of a single actin filament by glass needles. Nature. 1988 Jul 7;334(6177):74–76. [PubMed]
  • Jarcho JA, McKenna W, Pare JA, Solomon SD, Holcombe RF, Dickie S, Levi T, Donis-Keller H, Seidman JG, Seidman CE. Mapping a gene for familial hypertrophic cardiomyopathy to chromosome 14q1. N Engl J Med. 1989 Nov 16;321(20):1372–1378. [PubMed]
  • Thierfelder L, Watkins H, MacRae C, Lamas R, McKenna W, Vosberg HP, Seidman JG, Seidman CE. Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell. 1994 Jun 3;77(5):701–712. [PubMed]
  • Carrier L, Hengstenberg C, Beckmann JS, Guicheney P, Dufour C, Bercovici J, Dausse E, Berebbi-Bertrand I, Wisnewsky C, Pulvenis D, et al. Mapping of a novel gene for familial hypertrophic cardiomyopathy to chromosome 11. Nat Genet. 1993 Jul;4(3):311–313. [PubMed]

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