Myosin-10 also known as myosin heavy chain 10 or non-muscle myosin IIB (NM-IIB) is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the ''MYH10''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
Non-muscle myosins are expressed in a wide variety of tissues, but NM-IIB is the only non-muscle myosin II
isoform
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...
expressed in
cardiac muscle
Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle th ...
, where it localizes to
adherens junctions within
intercalated disc
Intercalated discs or lines of Eberth are microscopic identifying features of cardiac muscle. Cardiac muscle consists of individual heart muscle cells (cardiomyocytes) connected by intercalated discs to work as a single functional syncytium. By con ...
s. NM-IIB is essential for normal development of
cardiac muscle
Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle th ...
and for integrity of
intercalated disc
Intercalated discs or lines of Eberth are microscopic identifying features of cardiac muscle. Cardiac muscle consists of individual heart muscle cells (cardiomyocytes) connected by intercalated discs to work as a single functional syncytium. By con ...
s. Mutations in MYH10 have been identified in patients with
left atrial enlargement
Left atrial enlargement (LAE) or left atrial dilation refers to enlargement of the left atrium (LA) of the heart, and is a form of cardiomegaly.
Signs and symptoms
Left atrial enlargement can be mild, moderate or severe depending on the extent o ...
.
Structure
NM-IIB is 228.9 kDa
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
composed of 1976
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
s. NM-IIB has an
N-terminal
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
globular head that harbors the catalytically active, magnesium(Mg)-ATPase. The
C-terminal rod domain is an
alpha helical coiled-coil
A coiled coil is a structural motif in proteins in which 2–7
alpha helix, alpha-helices are coiled together like the strands of a rope. (Protein dimer, Dimers and Protein trimer, trimers are the most common types.) Many coiled coil-type protei ...
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.
The exception to this rule is the
alternatively spliced
Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be in ...
NM-IIB2
isoform
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...
, which has a 21
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
inserted into loop 2, near the actin-binding domain; actomyosin MgATPase activity of this
isoform
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...
is not enhanced by
phosphorylation
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
of the regulatory light chain
MLC20.
NM-IIB is part of the larger myosin II subfamily of
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
s, which also includes
skeletal muscle
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
,
cardiac muscle
Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle th ...
and
smooth muscle
Smooth muscle is an involuntary non-striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit mus ...
myosin
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.
The first myosin ...
s. 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
Smooth muscle is an involuntary non-striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit mus ...
myosin
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.
The first myosin ...
s, such as the permissive nature of
phosphorylation
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
of the 20 kDa regulatory light chain for
contraction
Contraction may refer to:
Linguistics
* Contraction (grammar), a shortened word
* Poetic contraction, omission of letters for poetic reasons
* Elision, omission of sounds
** Syncope (phonology), omission of sounds in a word
* Synalepha, merged ...
. In
skeletal muscle
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
and
cardiac muscle
Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle th ...
myosins, contraction is activated through
thin filament
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 ...
proteins
troponin and
tropomyosin
Tropomyosin is a two-stranded alpha-helical, coiled coil protein found in actin-based cytoskeletons.
Tropomyosin and the actin skeleton
All organisms contain organelles that provide physical integrity to their cells. These type of organelles ar ...
, whereas in NM-IIB and
smooth muscle
Smooth muscle is an involuntary non-striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit mus ...
myosin
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.
The first myosin ...
, contraction initiates via regulatory light chain (
MLC20)
phosphorylation
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
.
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
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to ...
-
calmodulin
Calmodulin (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells. It is an intracellular target of the secondary messenger Ca2+, and the bind ...
-dependent,
myosin light chain kinase
Myosin light-chain kinase also known as MYLK or MLCK is a serine/threonine-specific protein kinase that phosphorylates a specific myosin light chain, namely, the regulatory light chain of myosin II.
General structural features
While there ar ...
and the Rho-GTP dependent,
Rho kinase (ROCK). NM-IIB is
dephosphorylated by a myosin phosphatase.
Detailed kinetic studies on NM-IIB show that this
isoform
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...
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
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 ...
.
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. 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
Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle th ...
. Targeted gene disruption of NM-IIB resulted in approximately 65% embryonic lethality, and those that survived suffered from
congestive heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...
and died day 1 following birth. Feature observed in NM-IIB knockouts was an increase in the transverse diameters of
cardiomyocyte
Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that ...
s,
ventricular septal defects
A ventricular septal defect (VSD) is a defect in the ventricular septum, the wall dividing the left and right Ventricle (heart), ventricles of the heart. The extent of the opening may vary from pin size to complete absence of the ventricular sep ...
, as well as other muscular abnormalities. NM-IIB is expressed early during embryonic development in cardiomyocytes, 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.
In adult cardiomyocytes, NM-IIB redistributes from a diffuse
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
ic pattern in development to a localized
Z-disc
A sarcomere (Greek σάρξ ''sarx'' "flesh", μέρος ''meros'' "part") is the smallest functional unit of striated muscle tissue. It is the repeating unit between two Z-lines. Skeletal muscles are composed of tubular muscle cells (called musc ...
and
intercalated disc
Intercalated discs or lines of Eberth are microscopic identifying features of cardiac muscle. Cardiac muscle consists of individual heart muscle cells (cardiomyocytes) connected by intercalated discs to work as a single functional syncytium. By con ...
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
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
Z-discs, suggesting a specific function of NM-IIB in this cell type. NM-IIB may play a role in formation of mature
sarcomeres in
myofibril
A myofibril (also known as a muscle fibril or sarcostyle) is a basic rod-like organelle of a muscle cell. Skeletal muscles are composed of long, tubular cells known as muscle fibers, and these cells contain many chains of myofibrils. Each myofib ...
s. 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
Cytokinesis () is the part of the cell division process during which the cytoplasm of a single eukaryotic cell divides into two daughter cells. Cytoplasmic division begins during or after the late stages of nuclear division in mitosis and meios ...
; widened
adherens junctions; and progressive
hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy (HCM, or HOCM when obstructive) is a condition in which the heart becomes thickened without an obvious cause. The parts of the heart most commonly affected are the interventricular septum and the ventricles. This r ...
at 6 months. These data indicate that NM-IIB functions in ensuring the proper maintenance of
intercalated disc
Intercalated discs or lines of Eberth are microscopic identifying features of cardiac muscle. Cardiac muscle consists of individual heart muscle cells (cardiomyocytes) connected by intercalated discs to work as a single functional syncytium. By con ...
structures.
Clinical Significance
Single nucleotide polymorphism
In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently larg ...
s in ''MYH10'' were detected in patients with
left atrial enlargement
Left atrial enlargement (LAE) or left atrial dilation refers to enlargement of the left atrium (LA) of the heart, and is a form of cardiomegaly.
Signs and symptoms
Left atrial enlargement can be mild, moderate or severe depending on the extent o ...
. ''MYH10'' was identified to be a susceptibility gene using non-biased
genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ge ...
-wide linkage and peak-wide association analysis.
Interactions
MYH10 has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with:
*
MYL6
Myosin light polypeptide 6 is a protein that in humans is encoded by the ''MYL6'' gene.
Myosin is a hexameric ATPase cellular motor protein. It is composed of two heavy chains, two nonphosphorylatable alkali light chains, and two phosphorylatabl ...
and
*
MYL9
Myosin regulatory light polypeptide 9 is a protein that in humans is encoded by the ''MYL9'' gene.
Function
Myosin, a structural component of muscle, consists of two heavy chains and four light chains. The protein encoded by this gene is a myo ...
.
References
Further reading
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External links
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{{Cytoskeletal Proteins