MYH9

Last updated
MYH9
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases MYH9 , BDPLT6, DFNA17, EPSTS, FTNS, MHA, NMHC-II-A, NMMHC-IIA, NMMHCA, myosin, heavy chain 9, non-muscle, myosin heavy chain 9, MATINS
External IDs OMIM: 160775 MGI: 107717 HomoloGene: 129835 GeneCards: MYH9
Orthologs
SpeciesHumanMouse
Entrez

4627

17886

Ensembl

ENSG00000100345

ENSMUSG00000022443

UniProt

P35579
Q5BKV1

Q8VDD5

RefSeq (mRNA)

NM_002473

NM_022410

RefSeq (protein)

NP_002464
NP_002464.1

NP_071855

Location (UCSC) Chr 22: 36.28 – 36.39 Mb Chr 15: 77.64 – 77.73 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. [5] [6]

Contents

Non-muscle myosin IIA (NM IIA) is expressed in most cells and tissues where it participates in a variety of processes requiring contractile force, such as cytokinesis, cell migration, polarization and adhesion, maintenance of cell shape, and signal transduction. Myosin IIs are motor proteins that are part of a superfamily composed of more than 30 classes. [7] [8] [9] Class II myosins include muscle and non-muscle myosins that are organized as hexameric molecules consisting of two heavy chains (230 kDa), two regulatory light chains (20 KDa) controlling the myosin activity, and two essential light chains (17 kDa), which stabilize the heavy chain structure. [10] [11] [12] [13] [14]

Gene and protein structure

MYH9 is a large gene spanning more than 106 kilo base pairs on chromosome 22q12.3. It is composed of 41 exons with the first ATG of the open reading frame localized in exon 2 and the stop codon in exon 41. It encodes non-muscle myosin heavy chain IIA (NMHC IIA), a protein of 1,960 amino acids. Consistent with its wide expression in cells and tissues, the promoter region of MYH9 is typical of housekeeping genes having no TATA box but high GC content, with multiple GC boxes. MYH9 is a well-conserved gene through evolution. The mouse ortholog (Myh9) is localized in a syntenic region on chromosome 15 and has the same genomic organization as that of the human gene. It encodes a protein of the same length, with 97.1% amino acid identity with the human MYH9 protein. [15]

Like all class II myosins, the two NMHC IIAs dimerize producing an asymmetric molecular structure recognizable by two heads and a tail domain: the N-terminal half of each heavy chain generates the head domain, which consists of the globular motor domain and the neck domain, and the C-terminal halves of the two heavy chains together form the tail domain. [16] The motor domain, which is organized into four subdomains (SH3-like motif, the upper and the lower 50kDa subdomains, and the converter region) connected by flexible linkers, [17] interacts with filamentous actin to generate force through magnesium-dependent hydrolysis of ATP. The neck acts as a lever arm that amplifies the movement produced by conformational changes of the motor domain, and is the binding site for the light chains through two IQ motifs. The tail domain is fundamental for both dimerization of the heavy chains and formation of NM IIA functional filaments. Two heavy chains dimerize through the tail domain forming a long alpha-helical coiled-coil rod composed of typical heptad repeats. Dimers self-associate though the coiled-coil rods to form myosin filaments. The tail domain ends at the C-terminus with a 34-residue non-helical tailpiece. [14] [16]

Regulation of NM IIA structure and function

There are three paralogs of non-muscle myosin II (NM II), NM IIA, IIB, and IIC, with each having the heavy chain encoded on a different chromosome. All three paralogs appear to bind the same or very similar light chains and share basic properties as to structure and activation, but all three play distinct roles during vertebrate development and adulthood (for general reviews on NM IIs, see [11] [13] [14] ). All NM IIs have two important features: they are MgATPase enzymes that can hydrolyze ATP thereby converting chemical energy into mechanical movement. In addition, they can form bipolar filaments which can interact with and exert tension on actin filaments. These properties provide the basis for all NM II functions. The path to myosin filament formation, which is shared by NM II and smooth muscle myosin, starts with a folded inactive conformation of the NM II monomer which, upon phosphorylation of the 20 KDa light chain unfolds the molecule to produce a globular head region followed by an extended alpha-helical coiled-coil tail. [18] [19] [20] [21] The tail portion of the molecule can interact with other NM IIA hexamers to form bipolar filaments composed of 14-16 molecules.

Phosphorylation of the 20 KDa light chains on Serine 19 and Threonine 18 by a number of different kinases, but most prominently by Rho-dependent kinase and/or by the calcium-calmodulin-dependent myosin light chain kinase, not only linearizes the folded structure but removes the inhibition imposed on the MgATPase activity due to the folded conformation. In addition to phosphorylation of the 20 KDa light chains, the NMHC IIs can also be phosphorylated, but the sites phosphorylated differ among the paralogs. [10] In most cases phosphorylation of NMHC IIA can act to either dissociate the myosin filaments or to prevent filament formation.

In addition to phosphorylation, NM IIA filament assembly and localization can be modulated by interaction with other proteins including S100A4 and Lethal giant larvae (Lgl1). The former is a calcium binding protein and is also known as metastatin, a well-characterized metastatic factor. S100A4 expression is associated with enhanced cell migration through maintenance of cell polarization and inhibition of cell turning. [22] [23] Similar to heavy chain phosphorylation, in vitro binding of S100A to the carboxy-terminal end of the NM IIA coiled-coil region prevents filament formation and S100A4 binding to previously formed filaments promotes filament disassembly. The tumor suppressor protein Lgl1 also inhibits the ability of NM IIA to assemble into filaments in vitro. [24] [25] In addition, it regulates the cellular localization of NM IIA and contributes to the maturation of focal adhesions. Other proteins that are known to interact with NM IIA include the actin binding protein tropomyosin 4.2 [26] and a novel actin stress fiber associated protein, LIM and calponin-homology domains1 (LIMCH1). [27]

Functions specific to NM IIA

NM IIA plays a major role in early vertebrate development. Ablation of NM IIA in mice results in lethality by embryonic day (E) 6.5 due to abnormalities in the visceral endoderm which is disorganized due to a loss of E-cadherin mediated cell-cell adhesions. [28] Lacking a normal polarized columnar layer of endoderm, the abnormal visceral endoderm of NM IIA knockout embryos fails to support the critical step of gastrulation. However, the development of a normal functioning visceral endoderm does not specifically depend on NM IIA since its function can be restored by genetically replacing the NMHC IIA with cDNA encoding NMHC II B (or NMHC IIC) that is under control of the NMHC IIA promoter. [29] These “replacement” mice have a normal visceral endoderm and continue to proceed through gastrulation and undergo organogenesis. However, they die when they fail to develop a normal placenta. Absence of NM IIA results in a compact and underdeveloped labyrinthine layer in the placenta which lacks fetal blood vessel invasion. Moreover, mutant p.R702C NM IIA mice show similar defects in placental formation [30] and mice specifically ablated for NM IIA in the mouse trophoblast-lineage cells demonstrate placental defects similar to mice in which NMHC IIA is genetically replaced by NMHC IIB. [31] There are significant differences in the relative abundance of the three NM II paralogs in various cells and tissues. However, NM IIA appears to be the predominant paralog in both tissues and cells in humans and mice. Mass spectroscopy analysis of the relative abundance of NMHC IIs in mouse tissues and human cell lines [32] shows that NM IIA is predominant, although tissues like the heart vary from cell to cell; myocardial cells contain only NM IIB but NM IIA is more abundant in the non-myocyte cells. NM IIB is predominant in most parts of the brain and spinal cord but NM IIA is relatively more abundant in most other organs and cells lines. Both NM IIA and IIB are expressed early in development with NM IIC expression starting at E 11.5 in mice. Not only do most cells contain more than one paralog but there is evidence that the paralogs can co-assemble intracellularly into heterotypic filaments in a variety of settings in cultured cells. [33] [34] [35]

Clinical significance

MYH9-related disease. Mutations in MYH9 cause a Mendelian autosomal-dominant disorder known as MYH9-related disease (MYH9-RD). [36] [37] [38] [39] All affected individuals present congenital hematological alterations consisting in thrombocytopenia, platelet macrocytosis, and inclusions of the MYH9 protein in the cytoplasm of granulocytes. Most patients develop one or more non-congenital manifestations, including sensorineural deafness, kidney damage, presenile cataracts, and/or elevation of liver enzymes. [39] [40] [41] The term MYH9-RD encompasses four syndromic pictures that were considered for many years as distinct disorders, namely May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome. After the identification of MYH9 as the gene responsible for all of these entities, it was recognized that they actually represent different clinical presentations of the same disease, now known as MYH9-RD or MYH9 disorder. [38] MYH9-RD is a rare disease: prevalence is estimated around 3:1,000,000. The actual prevalence is expected to be higher, as mild forms are often discovered incidentally and patients are frequently misdiagnosed with other disorders. The disease has been reported worldwide and there is no evidence of variation in prevalence across ethnic populations. [42]

Thrombocytopenia can result in a variable degree of bleeding tendency. The majority of patients have no spontaneous bleeding or only mild cutaneous bleeding (easy bruising) and are at risk of significant hemorrhages only after surgery or other invasive procedures, deliveries, or trauma. Some patients have spontaneous mucosal bleeding, such as menorrhagia, epistaxis, and gum bleeding. [39] [40] Severe and life-threatening hemorrhages are not frequent. Platelets of MYH9-RD patients are characterized by a very large size: platelets larger than red blood cells (called "giant platelets") are always present at the examination of peripheral blood smears. [38] [43] Granulocyte inclusions of the NMHC IIA may be evident at the analysis of blood films after conventional staining as cytoplasmic basophilic (light blue) inclusions, called "Döhle-like bodies". [38] [39] More than 50% of MYH9-RD patients develop sensorineural hearing loss. [40] Severity of the hearing impairment is greatly variable, as it ranges from a mild hearing defect that occurs in mid or advanced age to a progressive hearing loss that is evident in the first years of life and rapidly evolves to severe deafness. [44] Kidney damage occurs in about 25% of patients. It presents with proteinuria and often progresses to kidney failure, which, in its most severe forms, may require dialysis and/or kidney transplantation. [40] Around 20% of patients develop presenile cataracts. About 50% of MYH9-RD patients present chronic or intermittent elevation of liver transaminases or gamma-glutamyl transferases: this alteration appears to be benign, as no patients showed evolution to liver dysfunction. [41]

Diagnosis of MYH9-RD is confirmed by the identification of the NMHC IIA inclusions in granulocytes through an immunofluorescence assay on peripheral blood smears and/or by the detection of the causative mutation through mutational screening of the MYH9 gene. [45] [46] [47] [48]

In most cases, MYH9-RD is caused by missense mutations affecting the head or tail domain of the NMHC IIA. Nonsense or frameshift alterations resulting in the deletion of a C-terminal fragment of the NMHC IIA (17 to 40 residues) are involved in approximately 20% of families. In-frame deletions or duplications have been identified in a few cases. [40] [45] [49] The disease is transmitted as an autosomal-dominant trait, however, about 35% of index cases are sporadic. [46] Sporadic forms mainly derive from de novo mutations; rare cases have been explained by germinal or somatic mosaicism. [50] [51] [52]

The incidence and the severity of the non-congenital manifestations of MYH9-RD correlate with the specific MYH9 mutation. The recent definition of genotype-phenotype correlations allows prediction of the clinical evolution of the disease in most cases. [40] [53] Genotype-phenotype correlations have been reported also for the severity of thrombocytopenia, platelet size, and the features of leukocyte inclusions. [40] [43] [54]

Within a phase 2 trial, eltrombopag, an agonist of the thrombopoietin receptor, significantly increased platelet count in 11 out of 12 patients affected with MYH9-RD. [55] ACE-inhibitors or angiotensin II receptor blockers may be effective in reducing proteinuria when given at the early stage of kidney involvement. [56] [57] Cochlear implantation is effective in restoring hearing function in MYH9-RD patients with severe/profound deafness. [58]

Role of MYH9 variants in other human diseases. Evidence obtained in animals indicates that MYH9 acts as a tumor suppressor gene. Silencing of Myh9 in the epithelial cells in mice was associated with the development of squamous cell carcinoma (SCC) of the skin and the head and neck. [59] In another mouse model, ablation of Myh9 in the tongue epithelium led to the development of tongue SCC. [60] In mice predisposed to invasive lobular breast carcinoma (ILBC) because of E-cadherin ablation, the inactivation of Myh9 led to the development of tumors recapitulating the features of human ILBC. [61] Some observations suggest that defective MYH9 expression is associated with oncogenesis and/or tumor progression in human SCC and ILBC, thus also supporting a role for MYH9 as a tumor suppressor in humans. [59] [61]

Genetic variations in MYH9 may be involved in predisposition to chronic kidney disease (CKD). A haplotype of MYH9 (haplotype E1) was previously associated with the increased prevalence of glomerulosclerosis [62] and non-diabetic end stage renal disease [63] in African Americans and in Hispanic Americans. [64] However, subsequent studies showed that this association is explained by strong linkage disequilibrium with two haplotypes (haplotypes G1 and G2) in the neighboring APOL1 gene. [65] [66] [67] Nevertheless, some studies suggest an association of single-nucleotide polymorphisms in MYH9 with CKD that appears to be independent of the linkage with APOL1 G1 and G2. [68] [69] [70]

Inherited MYH9 mutations may be responsible for non-syndromic hearing loss. [71] [72] [73]

Other interactions

MYH9 has been shown to interact with PRKCE. [74]

See also

Notes

Related Research Articles

<span class="mw-page-title-main">Actin</span> Family of proteins

Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over 100 μM; its mass is roughly 42 kDa, with a diameter of 4 to 7 nm.

<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">Tropomyosin</span> Protein

Tropomyosin is a two-stranded alpha-helical, coiled coil protein found in many animal and fungal cells. In animals, it is an important component of the muscular system which works in conjunction with troponin to regulate muscle contraction. It is present in smooth and striated muscle tissues, which can be found in various organs and body systems, including the heart, blood vessels, respiratory system, and digestive system. In fungi, tropomyosin is found in cell walls and helps maintain the structural integrity of cells.

<span class="mw-page-title-main">MYH7</span> Protein-coding gene in the species Homo sapiens

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 that forms the sarcomeres in cardiac muscle and plays a major role in cardiac muscle contraction.

<span class="mw-page-title-main">Myofilament</span> The two protein filaments of myofibrils in muscle cells

Myofilaments are the three protein filaments of myofibrils in muscle cells. The main proteins involved are myosin, actin, and titin. Myosin and actin are the contractile proteins and titin is an elastic protein. The myofilaments act together in muscle contraction, and in order of size are a thick one of mostly myosin, a thin one of mostly actin, and a very thin one of mostly titin.

<span class="mw-page-title-main">Telokin</span> Protein domain

Telokin is an abundant protein found in smooth-muscle. It is identical to the C-terminus of myosin light-chain kinase. Telokin may play a role in the stabilization of unphosphorylated smooth-muscle myosin filaments. Because of its origin as the C-terminal end of smooth muscle myosin light chain kinase, it is called "telokin".

<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> Protein-coding gene in the species Homo sapiens

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">ACTC1</span> Protein-coding gene in the species Homo sapiens

ACTC1 encodes cardiac muscle alpha actin. This isoform differs from the alpha actin that is expressed in skeletal muscle, ACTA1. Alpha cardiac actin is the major protein of the thin filament in cardiac sarcomeres, which are responsible for muscle contraction and generation of force to support the pump function of the heart.

<span class="mw-page-title-main">Myosin binding protein C, cardiac</span> Protein-coding gene in the species Homo sapiens

The myosin-binding protein C, cardiac-type is a protein that in humans is encoded by the MYBPC3 gene. This isoform is expressed exclusively in heart muscle during human and mouse development, and is distinct from those expressed in slow skeletal muscle (MYBPC1) and fast skeletal muscle (MYBPC2).

<span class="mw-page-title-main">TPM2</span> Protein-coding gene in the species Homo sapiens

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">MYH10</span> Protein-coding gene in the species Homo sapiens

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. 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.

<span class="mw-page-title-main">MYL2</span> Protein-coding gene in the species Homo sapiens

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">MYH6</span> Protein-coding gene in the species Homo sapiens

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">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">MYLK</span> Gene of the immunoglobulin superfamily

Myosin light chain kinase, smooth muscle also known as kinase-related protein (KRP) or telokin is an enzyme that in humans is encoded by the MYLK gene.

<span class="mw-page-title-main">MYL7</span> Protein-coding gene in the species Homo sapiens

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.

References

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