MYH10

Last updated
MYH10
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases MYH10 , NMMHC-IIB, NMMHCB, myosin, heavy chain 10, non-muscle, myosin heavy chain 10
External IDs OMIM: 160776 MGI: 1930780 HomoloGene: 55941 GeneCards: MYH10
Orthologs
SpeciesHumanMouse
Entrez

4628

77579

Ensembl

ENSG00000133026

ENSMUSG00000020900

UniProt

P35580

Q61879

RefSeq (mRNA)

NM_001256012
NM_001256095
NM_005964
NM_001375266

NM_175260

RefSeq (protein)

NP_001242941
NP_001243024
NP_005955
NP_001362195

NP_780469

Location (UCSC) Chr 17: 8.47 – 8.63 Mb Chr 11: 68.58 – 68.71 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. [5] [6] 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.

Contents

Structure

NM-IIB is 228.9 kDa protein composed of 1976 amino acids. [7] 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. [8] 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. [9]

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. [10]

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. [11]

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. [12]

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. [13] [14] 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. [15] NM-IIB is expressed early during embryonic development in cardiomyocytes, [16] 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. [17] [18]

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. [19] NM-IIB may play a role in formation of mature sarcomeres in myofibrils. [20] 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. [21] These data indicate that NM-IIB functions in ensuring the proper maintenance of intercalated disc structures. [22]

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. [23]

Interactions

MYH10 has been shown to interact with:

Related Research Articles

<span class="mw-page-title-main">Myosin</span> Superfamily of motor proteins

Myosins are a superfamily of motor proteins best known for their roles in muscle contraction and in a wide range of other motility processes in eukaryotes. They are ATP-dependent and responsible for actin-based motility.

<span class="mw-page-title-main">MYH16 gene</span> Pseudogene in the species Homo sapiens

The MYH16 gene encodes a protein called myosin heavy chain 16, which is a muscle protein in mammals. At least in primates, it is a specialized muscle protein found only in the temporalis and masseter muscles of the jaw. Myosin heavy chain proteins are important in muscle contraction, and if they are missing, the muscles will be smaller. In non-human primates, MYH16 is functional and the animals have powerful jaw muscles. In humans, the MYH16 gene has a mutation that causes the protein not to function. Although the exact importance of this change in accounting for differences between humans and other apes is not yet clear, such a change may be related to increased brain size and finer control of the jaw, which facilitates speech. It is not clear how the MYH16 mutation relates to other changes to the jaw and skull in early human evolution.

<span class="mw-page-title-main">MYH7</span>

MYH7 is a gene encoding a myosin heavy chain beta (MHC-β) isoform expressed primarily in the heart, but also in skeletal muscles. This isoform is distinct from the fast isoform of cardiac myosin heavy chain, MYH6, referred to as MHC-α. MHC-β is the major protein comprising the thick filament in cardiac muscle and plays a major role in cardiac muscle contraction.

<span class="mw-page-title-main">MYL9</span> Protein-coding gene in the species Homo sapiens

Myosin regulatory light polypeptide 9 is a protein that in humans is encoded by the MYL9 gene.

<span class="mw-page-title-main">TPM1</span>

Tropomyosin alpha-1 chain is a protein that in humans is encoded by the TPM1 gene. This gene is a member of the tropomyosin (Tm) family of highly conserved, widely distributed actin-binding proteins involved in the contractile system of striated and smooth muscles and the cytoskeleton of non-muscle cells.

<span class="mw-page-title-main">MYH9</span>

Myosin-9 also known as myosin, heavy chain 9, non-muscle or non-muscle myosin heavy chain IIa (NMMHC-IIA) is a protein which in humans is encoded by the MYH9 gene.

<span class="mw-page-title-main">TPM2</span>

β-Tropomyosin, also known as tropomyosin beta chain is a protein that in humans is encoded by the TPM2 gene. β-tropomyosin is striated muscle-specific coiled coil dimer that functions to stabilize actin filaments and regulate muscle contraction.

<span class="mw-page-title-main">MYL2</span>

Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (MLC-2) also known as the regulatory light chain of myosin (RLC) is a protein that in humans is encoded by the MYL2 gene. This cardiac ventricular RLC isoform is distinct from that expressed in skeletal muscle (MYLPF), smooth muscle (MYL12B) and cardiac atrial muscle (MYL7).

<span class="mw-page-title-main">Myosin-11</span>

Myosin-11 is a protein that in humans is encoded by the MYH11 gene.

<span class="mw-page-title-main">MYH6</span>

Myosin heavy chain, α isoform (MHC-α) is a protein that in humans is encoded by the MYH6 gene. This isoform is distinct from the ventricular/slow myosin heavy chain isoform, MYH7, referred to as MHC-β. MHC-α isoform is expressed predominantly in human cardiac atria, exhibiting only minor expression in human cardiac ventricles. It is the major protein comprising the cardiac muscle thick filament, and functions in cardiac muscle contraction. Mutations in MYH6 have been associated with late-onset hypertrophic cardiomyopathy, atrial septal defects and sick sinus syndrome.

<span class="mw-page-title-main">MYL3</span> Protein-coding gene in the species Homo sapiens

Myosin essential light chain (ELC), ventricular/cardiac isoform is a protein that in humans is encoded by the MYL3 gene. This cardiac ventricular/slow skeletal ELC isoform is distinct from that expressed in fast skeletal muscle (MYL1) and cardiac atrial muscle (MYL4). Ventricular ELC is part of the myosin molecule and is important in modulating cardiac muscle contraction.

<span class="mw-page-title-main">Myosin-2</span> Protein-coding gene in the species Homo sapiens

Myosin-2 is a protein that in humans is encoded by the MYH2 gene.

<span class="mw-page-title-main">MYL4</span> Protein-coding gene in the species Homo sapiens

Atrial Light Chain-1 (ALC-1), also known as Essential Light Chain, Atrial is a protein that in humans is encoded by the MYL4 gene. ALC-1 is expressed in fetal cardiac ventricular and fetal skeletal muscle, as well as fetal and adult cardiac atrial tissue. ALC-1 expression is reactivated in human ventricular myocardium in various cardiac muscle diseases, including hypertrophic cardiomyopathy, dilated cardiomyopathy, ischemic cardiomyopathy and congenital heart diseases.

<span class="mw-page-title-main">MYH1</span> Protein-coding gene in the species Homo sapiens

Myosin-1, also known as 'striated muscle myosin heavy chain 1', is a protein that in humans is encoded by the MYH1 gene. This gene is most highly expressed in fast type IIX/D muscle fibres of vertebrates and encodes a protein found uniquely in striated muscle; it is a class II myosin with a long coiled coil tail that dimerizes and should not be confused with 'Myosin 1' encoded by the MYO1 family of genes (MYO1A-MYO1H). Class I MYO1 genes function in many cell types throughout biology and are single-headed membrane-binding myosins that lack a long coiled coil tail.

<span class="mw-page-title-main">MYH14</span> Protein-coding gene in the species Homo sapiens

Myosin-14 is a protein that in humans is encoded by the MYH14 gene.

<span class="mw-page-title-main">MYL6</span> Protein-coding gene in the species Homo sapiens

Myosin light polypeptide 6 is a protein that in humans is encoded by the MYL6 gene.

<span class="mw-page-title-main">MYH8</span> Protein-coding gene in the species Homo sapiens

Myosin-8 is a protein that in humans is encoded by the MYH8 gene.

<span class="mw-page-title-main">MYL7</span>

Atrial Light Chain-2 (ALC-2) also known as Myosin regulatory light chain 2, atrial isoform (MLC2a) is a protein that in humans is encoded by the MYL7 gene. ALC-2 expression is restricted to cardiac muscle atria in healthy individuals, where it functions to modulate cardiac development and contractility. In human diseases, including hypertrophic cardiomyopathy, dilated cardiomyopathy, ischemic cardiomyopathy and others, ALC-2 expression is altered.

<span class="mw-page-title-main">MYH4</span> Protein-coding gene in the species Homo sapiens

Myosin-4 also known as myosin, heavy chain 4 is a protein which in humans is encoded by the MYH4 gene.

<span class="mw-page-title-main">Blebbistatin</span> Chemical compound

Blebbistatin is a myosin inhibitor mostly specific for myosin II. It is widely used in research to inhibit heart muscle myosin, non-muscle myosin II, and skeletal muscle myosin. Blebbistatin has been especially useful in optical mapping of the heart, and its recent use in cardiac muscle cell cultures has improved cell survival time. However, its adverse characteristics e.g. its cytotoxicity and blue-light instability or low solubility in water often make its application challenging. Recently its applicability was improved by chemical design and its derivatives overcome the limitations of blebbistatin. E.g. para-nitroblebbistatin and para-aminoblebbistatin are photostable, and they are neither cytotoxic nor fluorescent.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000133026 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000020900 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Simons M, Wang M, McBride OW, Kawamoto S, Yamakawa K, Gdula D, Adelstein RS, Weir L (Aug 1991). "Human nonmuscle myosin heavy chains are encoded by two genes located on different chromosomes". Circulation Research. 69 (2): 530–9. doi: 10.1161/01.res.69.2.530 . PMID   1860190.
  6. ↑ "Entrez Gene: MYH10 myosin, heavy chain 10, non-muscle".
  7. ↑ "Protein sequence of human MYH10 (Uniprot ID: P35580)". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Retrieved 17 July 2015.
  8. 1 2 3 Conti MA, Adelstein RS (Jan 2008). "Nonmuscle myosin II moves in new directions". Journal of Cell Science. 121 (Pt 1): 11–8. doi: 10.1242/jcs.007112 . PMID   18096687. S2CID   16367236.
  9. ↑ Kim KY, Kawamoto S, Bao J, Sellers JR, Adelstein RS (Apr 2008). "The B2 alternatively spliced isoform of nonmuscle myosin II-B lacks actin-activated MgATPase activity and in vitro motility". Biochemical and Biophysical Research Communications. 369 (1): 124–34. doi:10.1016/j.bbrc.2007.11.108. PMC   2366080 . PMID   18060863.
  10. ↑ Adelstein RS, Conti MA (Aug 1975). "Phosphorylation of platelet myosin increases actin-activated myosin ATPase activity". Nature. 256 (5518): 597–8. Bibcode:1975Natur.256..597A. doi:10.1038/256597a0. PMID   170529. S2CID   4169782.
  11. ↑ Ito M, Nakano T, Erdodi F, Hartshorne DJ (Apr 2004). "Myosin phosphatase: structure, regulation and function". Molecular and Cellular Biochemistry. 259 (1–2): 197–209. doi:10.1023/b:mcbi.0000021373.14288.00. PMID   15124925. S2CID   25196593.
  12. ↑ Wang F, Kovacs M, Hu A, Limouze J, Harvey EV, Sellers JR (Jul 2003). "Kinetic mechanism of non-muscle myosin IIB: functional adaptations for tension generation and maintenance". The Journal of Biological Chemistry. 278 (30): 27439–48. doi: 10.1074/jbc.M302510200 . PMID   12704189. S2CID   21026876.
  13. ↑ Vicente-Manzanares M, Ma X, Adelstein RS, Horwitz AR (Nov 2009). "Non-muscle myosin II takes centre stage in cell adhesion and migration". Nature Reviews Molecular Cell Biology. 10 (11): 778–90. doi:10.1038/nrm2786. PMC   2834236 . PMID   19851336.
  14. ↑ Walker A, Su H, Conti MA, Harb N, Adelstein RS, Sato N (7 September 2010). "Non-muscle myosin II regulates survival threshold of pluripotent stem cells". Nature Communications. 1 (6): 71. Bibcode:2010NatCo...1...71W. doi:10.1038/ncomms1074. PMC   3430968 . PMID   20842192.
  15. ↑ Tullio AN, Accili D, Ferrans VJ, Yu ZX, Takeda K, Grinberg A, Westphal H, Preston YA, Adelstein RS (Nov 1997). "Nonmuscle myosin II-B is required for normal development of the mouse heart". Proceedings of the National Academy of Sciences of the United States of America. 94 (23): 12407–12. Bibcode:1997PNAS...9412407T. doi: 10.1073/pnas.94.23.12407 . PMC   24969 . PMID   9356462.
  16. ↑ Wang A, Ma X, Conti MA, Liu C, Kawamoto S, Adelstein RS (Aug 2010). "Nonmuscle myosin II isoform and domain specificity during early mouse development". Proceedings of the National Academy of Sciences of the United States of America. 107 (33): 14645–50. Bibcode:2010PNAS..10714645W. doi: 10.1073/pnas.1004023107 . PMC   2930417 . PMID   20679233.
  17. ↑ Takeda K, Kishi H, Ma X, Yu ZX, Adelstein RS (Aug 2003). "Ablation and mutation of nonmuscle myosin heavy chain II-B results in a defect in cardiac myocyte cytokinesis". Circulation Research. 93 (4): 330–7. doi: 10.1161/01.RES.0000089256.00309.CB . PMID   12893741. S2CID   3175381.
  18. ↑ Ma X, Jana SS, Conti MA, Kawamoto S, Claycomb WC, Adelstein RS (Nov 2010). "Ablation of nonmuscle myosin II-B and II-C reveals a role for nonmuscle myosin II in cardiac myocyte karyokinesis". Molecular Biology of the Cell. 21 (22): 3952–62. doi:10.1091/mbc.E10-04-0293. PMC   2982113 . PMID   20861308.
  19. ↑ Takeda K, Yu ZX, Qian S, Chin TK, Adelstein RS, Ferrans VJ (May 2000). "Nonmuscle myosin II localizes to the Z-lines and intercalated discs of cardiac muscle and to the Z-lines of skeletal muscle". Cell Motility and the Cytoskeleton. 46 (1): 59–68. doi:10.1002/(SICI)1097-0169(200005)46:1<59::AID-CM6>3.0.CO;2-Q. PMID   10842333.
  20. ↑ Sanger JW, Kang S, Siebrands CC, Freeman N, Du A, Wang J, Stout AL, Sanger JM (2005). "How to build a myofibril". Journal of Muscle Research and Cell Motility. 26 (6–8): 343–54. doi:10.1007/s10974-005-9016-7. PMID   16465476. S2CID   9156161.
  21. ↑ Ma X, Takeda K, Singh A, Yu ZX, Zerfas P, Blount A, Liu C, Towbin JA, Schneider MD, Adelstein RS, Wei Q (Nov 2009). "Conditional ablation of nonmuscle myosin II-B delineates heart defects in adult mice". Circulation Research. 105 (11): 1102–9. doi:10.1161/CIRCRESAHA.109.200303. PMC   2792753 . PMID   19815823.
  22. ↑ Ma X, Adelstein RS (1 January 2012). "In vivo studies on nonmuscle myosin II expression and function in heart development". Frontiers in Bioscience. 17 (2): 545–55. doi:10.2741/3942. PMC   3476727 . PMID   22201759.
  23. ↑ Wang L, Di Tullio MR, Beecham A, Slifer S, Rundek T, Homma S, Blanton SH, Sacco RL (Aug 2010). "A comprehensive genetic study on left atrium size in Caribbean Hispanics identifies potential candidate genes in 17p10". Circulation: Cardiovascular Genetics. 3 (4): 386–92. doi:10.1161/CIRCGENETICS.110.938381. PMC   2923674 . PMID   20562446.

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