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 MYH10gene.[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.
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 helicalcoiled-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 musclemyosins. NM-IIB, and non-muscle myosins in general, are widely expressed in every tissue in humans.
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 muscleZ-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]
^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. PMID10842333.
^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. PMID16465476. S2CID9156161.
Strand D, Unger S, Corvi R, Hartenstein K, Schenkel H, Kalmes A, Merdes G, Neumann B, Krieg-Schneider F, Coy JF (Jul 1995). "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". Oncogene. 11 (2): 291–301. PMID7542763.
Maupin P, Phillips CL, Adelstein RS, Pollard TD (Nov 1994). "Differential localization of myosin-II isozymes in human cultured cells and blood cells". Journal of Cell Science. 107 (11): 3077–90. doi:10.1242/jcs.107.11.3077. PMID7699007.
Ford HL, Silver DL, Kachar B, Sellers JR, Zain SB (Dec 1997). "Effect of Mts1 on the structure and activity of nonmuscle myosin II". Biochemistry. 36 (51): 16321–7. doi:10.1021/bi971182l. PMID9405067.
Bastian P, Lang K, Niggemann B, Zaenker KS, Entschladen F (Jan 2005). "Myosin regulation in the migration of tumor cells and leukocytes within a three-dimensional collagen matrix". Cellular and Molecular Life Sciences. 62 (1): 65–76. doi:10.1007/s00018-004-4391-6. PMID15619008. S2CID38308190.
Nakasawa T, Takahashi M, Matsuzawa F, Aikawa S, Togashi Y, Saitoh T, Yamagishi A, Yazawa M (Jan 2005). "Critical regions for assembly of vertebrate nonmuscle myosin II". Biochemistry. 44 (1): 174–83. doi:10.1021/bi048807h. PMID15628858.
External links
Overview of all the structural information available in the PDB for UniProt: P35580 (Myosin-10) at the PDBe-KB.