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词条 MYH10
释义

  1. Structure

  2. Function

  3. Clinical Significance

  4. Interactions

  5. References

  6. Further reading

{{Infobox_gene}}

Myosin-10 also known as myosin heavy chain 10 or non-muscle myosin IIB (NM-IIB) is a protein that in humans is encoded by the MYH10 gene.[1][2] Non-muscle myosins are expressed in a wide variety of tissues, but NM-IIB is the only non-muscle myosin II isoform expressed in cardiac muscle, where it localizes to adherens junctions within intercalated discs. NM-IIB is essential for normal development of cardiac muscle and for integrity of intercalated discs. Mutations in MYH10 have been identified in patients with left atrial enlargement.

Structure

NM-IIB is 228.9 kDa protein composed of 1976 amino acids.[3] NM-IIB has an N-terminal globular head that harbors the catalytically active, magnesium(Mg)-ATPase. The C-terminal rod domain is an alpha helical coiled-coil that can multimerize with other myosin molecules to form a filament. Bound to the neck region of NM-IIB are two light chains; first, MLC17 stabilizes the molecule, while the second light chain, MLC20, modulates contraction.[4] The exception to this rule is the alternatively spliced NM-IIB2 isoform, which has a 21 amino acid inserted into loop 2, near the actin-binding domain; actomyosin MgATPase activity of this isoform is not enhanced by phosphorylation of the regulatory light chain MLC20.[5]

NM-IIB is part of the larger myosin II subfamily of proteins, which also includes skeletal muscle, cardiac muscle and smooth muscle myosins. NM-IIB, and non-muscle myosins in general, are widely expressed in every tissue in humans.

Function

NM-IIB has many properties that are similar to those of smooth muscle myosins, such as the permissive nature of phosphorylation of the 20 kDa regulatory light chain for contraction. In skeletal muscle and cardiac muscle myosins, contraction is activated through thin filament proteins troponin and tropomyosin, whereas in NM-IIB and smooth muscle myosin, contraction initiates via regulatory light chain (MLC20) phosphorylation.[6]

Various functions of NM-IIB require the phosphorylation of the regulatory light chain MLC20, including cell migration and cell adhesion. The two primary kinases catalyzing this reaction are the calcium-calmodulin-dependent, myosin light chain kinase and the Rho-GTP dependent, Rho kinase (ROCK). NM-IIB is dephosphorylated by a myosin phosphatase.[7]

Detailed kinetic studies on NM-IIB show that this isoform of non-muscle myosin II has a slower actomyosin ATPase cycle relative to other myosin II isoforms, and that the markedly high affinity of NM-IIB head for ADP as well as the slow rate of ADP release can mechanistically explain affinity this finding. These data indicate that NM-IIB spends a large amount of its kinetic cycle in a configuration where it is strongly attached to actin.[8]

NM-IIB, along with the other non-muscle myosin isoforms IIA and IIC, play a role in cell-cell and cell-matrix adhesion, cell migration, cell polarity, and embryonic stem cell apoptosis.[9][10] Insights into the function of NM-IIB specifically have come from studies employing transgenic animals. NM-IIB is clearly required for normal development of cardiac muscle. Targeted gene disruption of NM-IIB resulted in approximately 65% embryonic lethality, and those that survived suffered from congestive heart failure and died day 1 following birth. Feature observed in NM-IIB knockouts was an increase in the transverse diameters of cardiomyocytes, ventricular septal defects, as well as other muscular abnormalities.[11] NM-IIB is expressed early during embryonic development in cardiomyocytes,[12] and appears to play a role in karyokinesis; ablation of NM-IIB caused defects in chromatid segregation and mitotic spindle formation, as well as abnormal structure of centrosomes.[13][14]

In adult cardiomyocytes, NM-IIB redistributes from a diffuse cytoplasmic pattern in development to a localized Z-disc and intercalated disc distribution, where it colocalizes with alpha-actinin. NM-IIB is the only non-muscle myosin II isoform expressed in adult cardiac muscle (both IIa and IIB are expressed in skeletal muscle Z-discs, suggesting a specific function of NM-IIB in this cell type.[15] NM-IIB may play a role in formation of mature sarcomeres in myofibrils.[16] It appears that NM-IIB plays an essential role in maintaining normal adherens junction integrity and structure. A cardiac muscle-specific knockout of NM-IIB using the alpha-myosin heavy chain promoter-driven cre-recombinase develop enlarged cardiomyocytes, consistent with the defects previously observed with cytokinesis; widened adherens junctions; and progressive hypertrophic cardiomyopathy at 6 months.[17] These data indicate that NM-IIB functions in ensuring the proper maintenance of intercalated disc structures.[18]

Clinical Significance

Single nucleotide polymorphisms in MYH10 were detected in patients with left atrial enlargement. MYH10 was identified to be a susceptibility gene using non-biased genome-wide linkage and peak-wide association analysis.[19]

Interactions

MYH10 has been shown to interact with:

  • MYL6[4] and
  • MYL9.[4]

References

1. ^{{cite journal | vauthors = Simons M, Wang M, McBride OW, Kawamoto S, Yamakawa K, Gdula D, Adelstein RS, Weir L | title = Human nonmuscle myosin heavy chains are encoded by two genes located on different chromosomes | journal = Circulation Research | volume = 69 | issue = 2 | pages = 530–9 | date = Aug 1991 | pmid = 1860190 | pmc = | doi = 10.1161/01.res.69.2.530 }}
2. ^{{cite web | title = Entrez Gene: MYH10 myosin, heavy chain 10, non-muscle| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4628| accessdate = }}
3. ^{{cite web|title=Protein sequence of human MYH10 (Uniprot ID: P35580)|url=http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=P35580|website=Cardiac Organellar Protein Atlas Knowledgebase (COPaKB)|accessdate=17 July 2015}}
4. ^1 2 {{cite journal | vauthors = Conti MA, Adelstein RS | title = Nonmuscle myosin II moves in new directions | journal = Journal of Cell Science | volume = 121 | issue = Pt 1 | pages = 11–8 | date = Jan 2008 | pmid = 18096687 | doi = 10.1242/jcs.007112 }}
5. ^{{cite journal | vauthors = Kim KY, Kawamoto S, Bao J, Sellers JR, Adelstein RS | title = The B2 alternatively spliced isoform of nonmuscle myosin II-B lacks actin-activated MgATPase activity and in vitro motility | journal = Biochemical and Biophysical Research Communications | volume = 369 | issue = 1 | pages = 124–34 | date = Apr 2008 | pmid = 18060863 | doi = 10.1016/j.bbrc.2007.11.108 | pmc=2366080}}
6. ^{{cite journal | vauthors = Adelstein RS, Conti MA | title = Phosphorylation of platelet myosin increases actin-activated myosin ATPase activity | journal = Nature | volume = 256 | issue = 5518 | pages = 597–8 | date = Aug 1975 | pmid = 170529 | doi=10.1038/256597a0}}
7. ^{{cite journal | vauthors = Ito M, Nakano T, Erdodi F, Hartshorne DJ | title = Myosin phosphatase: structure, regulation and function | journal = Molecular and Cellular Biochemistry | volume = 259 | issue = 1–2 | pages = 197–209 | date = Apr 2004 | pmid = 15124925 | doi=10.1023/b:mcbi.0000021373.14288.00}}
8. ^{{cite journal | vauthors = Wang F, Kovacs M, Hu A, Limouze J, Harvey EV, Sellers JR | title = Kinetic mechanism of non-muscle myosin IIB: functional adaptations for tension generation and maintenance | journal = The Journal of Biological Chemistry | volume = 278 | issue = 30 | pages = 27439–48 | date = Jul 2003 | pmid = 12704189 | doi = 10.1074/jbc.M302510200 }}
9. ^{{cite journal | vauthors = Vicente-Manzanares M, Ma X, Adelstein RS, Horwitz AR | title = Non-muscle myosin II takes centre stage in cell adhesion and migration | journal = Nature Reviews Molecular Cell Biology | volume = 10 | issue = 11 | pages = 778–90 | date = Nov 2009 | pmid = 19851336 | doi = 10.1038/nrm2786 | pmc=2834236}}
10. ^{{cite journal | vauthors = Walker A, Su H, Conti MA, Harb N, Adelstein RS, Sato N | title = Non-muscle myosin II regulates survival threshold of pluripotent stem cells | journal = Nature Communications | volume = 1 | pages = 71 | date = 7 September 2010 | pmid = 20842192 | doi = 10.1038/ncomms1074 | pmc=3430968}}
11. ^{{cite journal | vauthors = Tullio AN, Accili D, Ferrans VJ, Yu ZX, Takeda K, Grinberg A, Westphal H, Preston YA, Adelstein RS | title = Nonmuscle myosin II-B is required for normal development of the mouse heart | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 23 | pages = 12407–12 | date = Nov 1997 | pmid = 9356462 | doi=10.1073/pnas.94.23.12407 | pmc=24969}}
12. ^{{cite journal | vauthors = Wang A, Ma X, Conti MA, Liu C, Kawamoto S, Adelstein RS | title = Nonmuscle myosin II isoform and domain specificity during early mouse development | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 33 | pages = 14645–50 | date = Aug 2010 | pmid = 20679233 | doi = 10.1073/pnas.1004023107 | pmc=2930417}}
13. ^{{cite journal | vauthors = Takeda K, Kishi H, Ma X, Yu ZX, Adelstein RS | title = Ablation and mutation of nonmuscle myosin heavy chain II-B results in a defect in cardiac myocyte cytokinesis | journal = Circulation Research | volume = 93 | issue = 4 | pages = 330–7 | date = Aug 2003 | pmid = 12893741 | doi = 10.1161/01.RES.0000089256.00309.CB }}
14. ^{{cite journal | vauthors = Ma X, Jana SS, Conti MA, Kawamoto S, Claycomb WC, Adelstein RS | title = Ablation of nonmuscle myosin II-B and II-C reveals a role for nonmuscle myosin II in cardiac myocyte karyokinesis | journal = Molecular Biology of the Cell | volume = 21 | issue = 22 | pages = 3952–62 | date = Nov 2010 | pmid = 20861308 | doi = 10.1091/mbc.E10-04-0293 | pmc=2982113}}
15. ^{{cite journal | vauthors = Takeda K, Yu ZX, Qian S, Chin TK, Adelstein RS, Ferrans VJ | title = Nonmuscle myosin II localizes to the Z-lines and intercalated discs of cardiac muscle and to the Z-lines of skeletal muscle | journal = Cell Motility and the Cytoskeleton | volume = 46 | issue = 1 | pages = 59–68 | date = May 2000 | pmid = 10842333 | doi = 10.1002/(SICI)1097-0169(200005)46:1<59::AID-CM6>3.0.CO;2-Q }}
16. ^{{cite journal | vauthors = Sanger JW, Kang S, Siebrands CC, Freeman N, Du A, Wang J, Stout AL, Sanger JM | title = How to build a myofibril | journal = Journal of Muscle Research and Cell Motility | volume = 26 | issue = 6–8 | pages = 343–54 | date = 2005 | pmid = 16465476 | doi = 10.1007/s10974-005-9016-7 }}
17. ^{{cite journal | vauthors = Ma X, Takeda K, Singh A, Yu ZX, Zerfas P, Blount A, Liu C, Towbin JA, Schneider MD, Adelstein RS, Wei Q | title = Conditional ablation of nonmuscle myosin II-B delineates heart defects in adult mice | journal = Circulation Research | volume = 105 | issue = 11 | pages = 1102–9 | date = Nov 2009 | pmid = 19815823 | doi = 10.1161/CIRCRESAHA.109.200303 | pmc=2792753}}
18. ^{{cite journal | vauthors = Ma X, Adelstein RS | title = In vivo studies on nonmuscle myosin II expression and function in heart development | journal = Frontiers in Bioscience | volume = 17 | pages = 545–55 | date = 1 January 2012 | pmid = 22201759 | doi=10.2741/3942 | pmc=3476727}}
19. ^{{cite journal | vauthors = Wang L, Di Tullio MR, Beecham A, Slifer S, Rundek T, Homma S, Blanton SH, Sacco RL | title = A comprehensive genetic study on left atrium size in Caribbean Hispanics identifies potential candidate genes in 17p10 | journal = Circulation: Cardiovascular Genetics | volume = 3 | issue = 4 | pages = 386–92 | date = Aug 2010 | pmid = 20562446 | doi = 10.1161/CIRCGENETICS.110.938381 | pmc=2923674}}

Further reading

{{refbegin|33em}}
  • {{cite journal | vauthors = Phillips CL, Yamakawa K, Adelstein RS | title = Cloning of the cDNA encoding human nonmuscle myosin heavy chain-B and analysis of human tissues with isoform-specific antibodies | journal = Journal of Muscle Research and Cell Motility | volume = 16 | issue = 4 | pages = 379–89 | date = Aug 1995 | pmid = 7499478 | doi = 10.1007/BF00114503 }}
  • {{cite journal | vauthors = Strand D, Unger S, Corvi R, Hartenstein K, Schenkel H, Kalmes A, Merdes G, Neumann B, Krieg-Schneider F, Coy JF | title = A human homologue of the Drosophila tumour suppressor gene l(2)gl maps to 17p11.2-12 and codes for a cytoskeletal protein that associates with nonmuscle myosin II heavy chain | journal = Oncogene | volume = 11 | issue = 2 | pages = 291–301 | date = Jul 1995 | pmid = 7542763 | doi = }}
  • {{cite journal | vauthors = Maupin P, Phillips CL, Adelstein RS, Pollard TD | title = Differential localization of myosin-II isozymes in human cultured cells and blood cells | journal = Journal of Cell Science | volume = 107 | issue = 11 | pages = 3077–90 | date = Nov 1994 | pmid = 7699007 | doi = }}
  • {{cite journal | vauthors = Itoh K, Adelstein RS | title = Neuronal cell expression of inserted isoforms of vertebrate nonmuscle myosin heavy chain II-B | journal = The Journal of Biological Chemistry | volume = 270 | issue = 24 | pages = 14533–40 | date = Jun 1995 | pmid = 7782316 | doi = 10.1074/jbc.270.24.14533 }}
  • {{cite journal | vauthors = Aikawa M, Sivam PN, Kuro-o M, Kimura K, Nakahara K, Takewaki S, Ueda M, Yamaguchi H, Yazaki Y, Periasamy M | title = Human smooth muscle myosin heavy chain isoforms as molecular markers for vascular development and atherosclerosis | journal = Circulation Research | volume = 73 | issue = 6 | pages = 1000–12 | date = Dec 1993 | pmid = 7916668 | doi = 10.1161/01.res.73.6.1000 }}
  • {{cite journal | vauthors = Shoeman RL, Sachse C, Höner B, Mothes E, Kaufmann M, Traub P | title = Cleavage of human and mouse cytoskeletal and sarcomeric proteins by human immunodeficiency virus type 1 protease. Actin, desmin, myosin, and tropomyosin | journal = The American Journal of Pathology | volume = 142 | issue = 1 | pages = 221–30 | date = Jan 1993 | pmid = 8424456 | pmc = 1886840 | doi = }}
  • {{cite journal | vauthors = Kawamoto S | title = Neuron-specific alternative splicing of nonmuscle myosin II heavy chain-B pre-mRNA requires a cis-acting intron sequence | journal = The Journal of Biological Chemistry | volume = 271 | issue = 30 | pages = 17613–6 | date = Jul 1996 | pmid = 8663598 | doi = 10.1074/jbc.271.30.17613 }}
  • {{cite journal | vauthors = Weir L, Chen D | title = Characterization of the nonmuscle myosin heavy chain IIB promoter: regulation by E2F | journal = Gene Expression | volume = 6 | issue = 1 | pages = 45–57 | year = 1997 | pmid = 8931991 | doi = }}
  • {{cite journal | vauthors = Ford HL, Silver DL, Kachar B, Sellers JR, Zain SB | title = Effect of Mts1 on the structure and activity of nonmuscle myosin II | journal = Biochemistry | volume = 36 | issue = 51 | pages = 16321–7 | date = Dec 1997 | pmid = 9405067 | doi = 10.1021/bi971182l }}
  • {{cite journal | vauthors = Lin VK, Wang D, Lee IL, Vasquez D, Fagelson JE, McConnell JD | title = Myosin heavy chain gene expression in normal and hyperplastic human prostate tissue | journal = The Prostate | volume = 44 | issue = 3 | pages = 193–203 | date = Aug 2000 | pmid = 10906735 | doi = 10.1002/1097-0045(20000801)44:3<193::AID-PROS3>3.0.CO;2-A }}
  • {{cite journal | vauthors = Nguyen M, Breckenridge DG, Ducret A, Shore GC | title = Caspase-resistant BAP31 inhibits fas-mediated apoptotic membrane fragmentation and release of cytochrome c from mitochondria | journal = Molecular and Cellular Biology | volume = 20 | issue = 18 | pages = 6731–40 | date = Sep 2000 | pmid = 10958671 | pmc = 86192 | doi = 10.1128/MCB.20.18.6731-6740.2000 }}
  • {{cite journal | vauthors = Wei Q, Adelstein RS | title = Conditional expression of a truncated fragment of nonmuscle myosin II-A alters cell shape but not cytokinesis in HeLa cells | journal = Molecular Biology of the Cell | volume = 11 | issue = 10 | pages = 3617–27 | date = Oct 2000 | pmid = 11029059 | pmc = 15019 | doi = 10.1091/mbc.11.10.3617 }}
  • {{cite journal | vauthors = Huang H, Paliouras M, Rambaldi I, Lasko P, Featherstone M | title = Nonmuscle myosin promotes cytoplasmic localization of PBX | journal = Molecular and Cellular Biology | volume = 23 | issue = 10 | pages = 3636–45 | date = May 2003 | pmid = 12724421 | pmc = 164772 | doi = 10.1128/MCB.23.10.3636-3645.2003 }}
  • {{cite journal | vauthors = Trinczek B, Brajenovic M, Ebneth A, Drewes G | title = MARK4 is a novel microtubule-associated proteins/microtubule affinity-regulating kinase that binds to the cellular microtubule network and to centrosomes | journal = The Journal of Biological Chemistry | volume = 279 | issue = 7 | pages = 5915–23 | date = Feb 2004 | pmid = 14594945 | doi = 10.1074/jbc.M304528200 }}
  • {{cite journal | vauthors = Straight AF, Field CM, Mitchison TJ | title = Anillin binds nonmuscle myosin II and regulates the contractile ring | journal = Molecular Biology of the Cell | volume = 16 | issue = 1 | pages = 193–201 | date = Jan 2005 | pmid = 15496454 | pmc = 539163 | doi = 10.1091/mbc.E04-08-0758 }}
  • {{cite journal | vauthors = Bastian P, Lang K, Niggemann B, Zaenker KS, Entschladen F | title = Myosin regulation in the migration of tumor cells and leukocytes within a three-dimensional collagen matrix | journal = Cellular and Molecular Life Sciences | volume = 62 | issue = 1 | pages = 65–76 | date = Jan 2005 | pmid = 15619008 | doi = 10.1007/s00018-004-4391-6 }}
  • {{cite journal | vauthors = Nakasawa T, Takahashi M, Matsuzawa F, Aikawa S, Togashi Y, Saitoh T, Yamagishi A, Yazawa M | title = Critical regions for assembly of vertebrate nonmuscle myosin II | journal = Biochemistry | volume = 44 | issue = 1 | pages = 174–83 | date = Jan 2005 | pmid = 15628858 | doi = 10.1021/bi048807h }}
{{refend}}{{Cytoskeletal Proteins}}
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