MuSK protein
Encyclopedia
MuSK is a receptor tyrosine kinase
required for the formation of the neuromuscular junction
. It is activated by a nerve-derived proteoglycan
called agrin
.
. This protein binds to several receptors on the surface of skeletal muscle
. The receptor that seems to be required for formation of the neuromuscular junction
(NMJ), which comprises the nerve-muscle synapse
, is called MuSK (Muscle-specific kinase). MuSK is a receptor tyrosine kinase - meaning that it induces cellular signaling by causing the addition of phosphate molecules to particular tyrosines on itself, and on proteins that bind the cytoplasmic domain of the receptor.
The requirement for MuSK in the formation of the NMJ was primarily demonstrated by mouse ("knockout") studies. In mice that are deficient for either agrin or MuSK, the neuromuscular junction does not form. Many other proteins also comprise the NMJ, and are required to maintain its integrity. For example,
MuSK also binds a protein called "downstream-of-tyrosine-kinase-7" (Dok-7). Dok-7's PTB domain binds phosphorylated MuSK, which acts to stabilize active MuSK or alternatively enhance MuSK's own kinase activity.
, MuSK signals via the proteins called Casein kinase 2
(CK2), Dok-7
and rapsyn, to induce "clustering" of acetylcholine receptors (AChR
). Both CK2 and Dok-7
are required for MuSK induced formation of the neuromuscular junction
, since mice lacking Dok-7
failed to form AChR
clusters or neuromuscular synapses, and since downregulation of CK2 also impedes recruitment of AChR to the primary MuSK scaffold. In addition to the proteins mentioned, other proteins are then gathered, to form the endplate to the neuromuscular junction. The nerve terminates onto the endplate, forming the neuromuscular junction - a structure required to transmit nerve impulses to the muscle, and thus initiating muscle contraction.
not demonstrating antibodies to the acetylcholine receptor
(sero-negative). The phenotype of these patients appears to be different from many other myasthenic patients; more likely women, less eye involvement, more likely to have weakness of neck and oropharynx and more likely to be African-American in ethnicity.
Receptor tyrosine kinase
Receptor tyrosine kinases s are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins....
required for the formation of the neuromuscular junction
Neuromuscular junction
A neuromuscular junction is the synapse or junction of the axon terminal of a motor neuron with the motor end plate, the highly-excitable region of muscle fiber plasma membrane responsible for initiation of action potentials across the muscle's surface, ultimately causing the muscle to contract...
. It is activated by a nerve-derived proteoglycan
Proteoglycan
Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan chain. The point of attachment is a Ser residue to which the glycosaminoglycan is joined through a tetrasaccharide bridge...
called agrin
Agrin
Agrin is a large proteoglycan whose best characterised role is in the development of the neuromuscular junction during embryogenesis. Agrin is named based on its involvement in the aggregation of acetylcholine receptors during synaptogenesis. In humans, this protein is encoded by the AGRN...
.
MuSK is required for formation of the Neuromuscular Junction
During development, the growing end of motor neuron axons secrete a protein called agrinAgrin
Agrin is a large proteoglycan whose best characterised role is in the development of the neuromuscular junction during embryogenesis. Agrin is named based on its involvement in the aggregation of acetylcholine receptors during synaptogenesis. In humans, this protein is encoded by the AGRN...
. This protein binds to several receptors on the surface of skeletal muscle
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...
. The receptor that seems to be required for formation of the neuromuscular junction
Neuromuscular junction
A neuromuscular junction is the synapse or junction of the axon terminal of a motor neuron with the motor end plate, the highly-excitable region of muscle fiber plasma membrane responsible for initiation of action potentials across the muscle's surface, ultimately causing the muscle to contract...
(NMJ), which comprises the nerve-muscle synapse
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
, is called MuSK (Muscle-specific kinase). MuSK is a receptor tyrosine kinase - meaning that it induces cellular signaling by causing the addition of phosphate molecules to particular tyrosines on itself, and on proteins that bind the cytoplasmic domain of the receptor.
The requirement for MuSK in the formation of the NMJ was primarily demonstrated by mouse ("knockout") studies. In mice that are deficient for either agrin or MuSK, the neuromuscular junction does not form. Many other proteins also comprise the NMJ, and are required to maintain its integrity. For example,
MuSK also binds a protein called "downstream-of-tyrosine-kinase-7" (Dok-7). Dok-7's PTB domain binds phosphorylated MuSK, which acts to stabilize active MuSK or alternatively enhance MuSK's own kinase activity.
MuSK signaling
Upon activation by its ligand agrinAgrin
Agrin is a large proteoglycan whose best characterised role is in the development of the neuromuscular junction during embryogenesis. Agrin is named based on its involvement in the aggregation of acetylcholine receptors during synaptogenesis. In humans, this protein is encoded by the AGRN...
, MuSK signals via the proteins called Casein kinase 2
Casein kinase 2
The Casein kinase 2 is a serine/threonine-selective protein kinase that is a tetramer of two alpha subunits and two beta subunits. The alpha subunits have the catalytic kinase domain...
(CK2), Dok-7
Dok-7
Dok-7 is a non-catalytic cytoplasmic adaptor protein that is expressed specifically in muscle and is essential for the formation of neuromuscular synapses. Further, Dok-7 contains pleckstrin homology and phosphotyrosine-binding domains that are critical for Dok-7 function...
and rapsyn, to induce "clustering" of acetylcholine receptors (AChR
ACHR
ACHR may refer to:*American Convention on Human Rights*Asian Centre for Human Rights*Acetylcholine receptor...
). Both CK2 and Dok-7
Dok-7
Dok-7 is a non-catalytic cytoplasmic adaptor protein that is expressed specifically in muscle and is essential for the formation of neuromuscular synapses. Further, Dok-7 contains pleckstrin homology and phosphotyrosine-binding domains that are critical for Dok-7 function...
are required for MuSK induced formation of the neuromuscular junction
Neuromuscular junction
A neuromuscular junction is the synapse or junction of the axon terminal of a motor neuron with the motor end plate, the highly-excitable region of muscle fiber plasma membrane responsible for initiation of action potentials across the muscle's surface, ultimately causing the muscle to contract...
, since mice lacking Dok-7
Dok-7
Dok-7 is a non-catalytic cytoplasmic adaptor protein that is expressed specifically in muscle and is essential for the formation of neuromuscular synapses. Further, Dok-7 contains pleckstrin homology and phosphotyrosine-binding domains that are critical for Dok-7 function...
failed to form AChR
ACHR
ACHR may refer to:*American Convention on Human Rights*Asian Centre for Human Rights*Acetylcholine receptor...
clusters or neuromuscular synapses, and since downregulation of CK2 also impedes recruitment of AChR to the primary MuSK scaffold. In addition to the proteins mentioned, other proteins are then gathered, to form the endplate to the neuromuscular junction. The nerve terminates onto the endplate, forming the neuromuscular junction - a structure required to transmit nerve impulses to the muscle, and thus initiating muscle contraction.
MuSK's role in disease
Antibodies directed against this protein are found in those patients with myasthenia gravisMyasthenia gravis
Myasthenia gravis is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability...
not demonstrating antibodies to the acetylcholine receptor
Acetylcholine receptor
An acetylcholine receptor is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter.-Classification:...
(sero-negative). The phenotype of these patients appears to be different from many other myasthenic patients; more likely women, less eye involvement, more likely to have weakness of neck and oropharynx and more likely to be African-American in ethnicity.