Skip Header

You are using a version of Internet Explorer that may not display all features of this website. Please upgrade to a modern browser.
Contribute Send feedback
Read comments (?) or add your own

Q62838 (MUSK_RAT) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 121. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Muscle, skeletal receptor tyrosine protein kinase

EC=2.7.10.1
Alternative name(s):
Muscle-specific tyrosine protein kinase receptor
Short name=MuSK
Short name=Muscle-specific kinase receptor
Gene names
Name:Musk
OrganismRattus norvegicus (Rat) [Reference proteome]
Taxonomic identifier10116 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus

Protein attributes

Sequence length868 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Receptor tyrosine kinase which plays a central role in the formation and the maintenance of the neuromuscular junction (NMJ), the synapse between the motor neuron and the skeletal muscle. Recruitment of AGRIN by LRP4 to the MUSK signaling complex induces phosphorylation and activation of MUSK, the kinase of the complex. The activation of MUSK in myotubes regulates the formation of NMJs through the regulation of different processes including the specific expression of genes in subsynaptic nuclei, the reorganization of the actin cytoskeleton and the clustering of the acetylcholine receptors (AChR) in the postsynaptic membrane. May regulate AChR phosphorylation and clustering through activation of ABL1 and Src family kinases which in turn regulate MUSK. DVL1 and PAK1 that form a ternary complex with MUSK are also important for MUSK-dependent regulation of AChR clustering. May positively regulate Rho family GTPases through FNTA. Mediates the phosphorylation of FNTA which promotes prenylation, recruitment to membranes and activation of RAC1 a regulator of the actin cytoskeleton and of gene expression. Other effectors of the MUSK signaling include DNAJA3 which functions downstream of MUSK. May also play a role within the central nervous system by mediating cholinergic responses, synaptic plasticity and memory formation. Ref.2 Ref.7

Catalytic activity

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.

Enzyme regulation

Positively regulated by CK2 By similarity. Ref.5

Subunit structure

Monomer By similarity. Homodimer Probable. Interacts with LRP4; the heterodimer forms an AGRIN receptor complex that binds AGRIN resulting in activation of MUSK. Forms a heterotetramer composed of 2 DOK7 and 2 MUSK molecules which facilitates MUSK trans-autophosphorylation on tyrosine residue and activation. Interacts (via cytoplasmic part) with DOK7 (via IRS-type PTB domain); requires MUSK phosphorylation. Interacts with DVL1 (via DEP domain); the interaction is direct and mediates the formation of a DVL1, MUSK and PAK1 ternary complex involved in AChR clustering By similarity. Interacts with PDZRN3; this interaction is enhanced by agrin By similarity. Interacts with FNTA; the interaction is direct and mediates AGRIN-induced phosphorylation and activation of FNTA By similarity. Interacts with CSNK2B; mediates regulation by CK2 By similarity. Interacts (via the cytoplasmic domain) with DNAJA3. Interacts with NSF; may regulate MUSK endocytosis and activity By similarity. Interacts with CAV3; may regulate MUSK signaling By similarity. Interacts with RNF31 By similarity. Ref.3 Ref.4 Ref.5 Ref.7 Ref.8

Subcellular location

Cell junctionsynapsepostsynaptic cell membrane; Single-pass type I membrane protein Probable. Note: Localizes to the postsynaptic cell membrane of the neuromuscular junction Probable. Ref.7

Tissue specificity

Muscle specific. Ref.1

Developmental stage

From E14.0 day, expressed in developing myotomes. Once the muscle is innervated, localized to the neuromuscular junction (NMJ), where its expression is restricted to synaptic nuclei. Expression drops after birth. Ref.1

Induction

Up-regulated upon denervation (at protein level). Ref.1 Ref.5

Post-translational modification

Ubiquitinated by PDZRN3. Ubiquitination promotes endocytosis and lysosomal degradation By similarity.

Phosphorylated. Phosphorylation is induced by AGRIN. Autophosphorylation at Tyr-553 is required for interaction with DOK7 which in turn stimulates the phosphorylation and the activation of MUSK By similarity. Ref.5 Ref.7

Neddylated By similarity.

Sequence similarities

Belongs to the protein kinase superfamily. Tyr protein kinase family.

Contains 1 FZ (frizzled) domain.

Contains 3 Ig-like C2-type (immunoglobulin-like) domains.

Contains 1 protein kinase domain.

Ontologies

Keywords
   Biological processDifferentiation
   Cellular componentCell junction
Cell membrane
Membrane
Postsynaptic cell membrane
Synapse
   DomainImmunoglobulin domain
Repeat
Signal
Transmembrane
Transmembrane helix
   LigandATP-binding
Nucleotide-binding
   Molecular functionDevelopmental protein
Kinase
Muscle protein
Receptor
Transferase
Tyrosine-protein kinase
   PTMDisulfide bond
Glycoprotein
Phosphoprotein
Ubl conjugation
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processcell differentiation

Inferred from electronic annotation. Source: UniProtKB-KW

cochlea development

Inferred from expression pattern PubMed 18420419. Source: RGD

long-term synaptic potentiation

Inferred from mutant phenotype Ref.2. Source: RGD

memory

Inferred from mutant phenotype Ref.2. Source: RGD

negative regulation of gene expression

Inferred from direct assay PubMed 15604144. Source: RGD

neuromuscular junction development

Inferred from expression pattern Ref.1. Source: RGD

peptidyl-tyrosine phosphorylation

Inferred from direct assay Ref.6Ref.5. Source: GOC

positive regulation of gene expression

Inferred from mutant phenotype Ref.2. Source: RGD

positive regulation of peptidyl-tyrosine phosphorylation

Inferred from direct assay PubMed 18436384. Source: RGD

positive regulation of protein phosphorylation

Inferred from direct assay PubMed 18436384. Source: RGD

positive regulation of synaptic growth at neuromuscular junction

Inferred from mutant phenotype PubMed 14749715. Source: RGD

positive regulation of synaptic transmission, cholinergic

Inferred from mutant phenotype Ref.2. Source: RGD

protein autophosphorylation

Inferred from direct assay PubMed 16818610. Source: RGD

receptor clustering

Inferred from mutant phenotype PubMed 16818610. Source: RGD

regulation of synaptic growth at neuromuscular junction

Inferred from sequence or structural similarity. Source: UniProtKB

response to axon injury

Inferred from expression pattern PubMed 9698449. Source: RGD

response to electrical stimulus

Inferred from mutant phenotype Ref.2. Source: RGD

response to muscle activity

Inferred from expression pattern PubMed 9698449. Source: RGD

retina development in camera-type eye

Inferred from expression pattern PubMed 16899069. Source: RGD

   Cellular_componentcell junction

Inferred from electronic annotation. Source: UniProtKB-KW

cell projection

Inferred from direct assay PubMed 16899069. Source: RGD

external side of plasma membrane

Inferred from direct assay Ref.7. Source: RGD

integral component of membrane

Inferred from electronic annotation. Source: UniProtKB-KW

neuromuscular junction

Inferred from direct assay PubMed 9698449. Source: RGD

plasma membrane

Inferred from sequence or structural similarity. Source: UniProtKB

postsynaptic membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

protein kinase binding

Inferred from physical interaction PubMed 16818610. Source: RGD

protein tyrosine kinase activity

Inferred from direct assay Ref.5. Source: UniProtKB

transmembrane receptor protein tyrosine kinase activity

Inferred from electronic annotation. Source: UniProtKB-EC

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2121 Potential
Chain22 – 868847Muscle, skeletal receptor tyrosine protein kinase
PRO_0000024448

Regions

Topological domain22 – 494473Extracellular Potential
Transmembrane495 – 51521Helical; Potential
Topological domain516 – 868353Cytoplasmic Potential
Domain28 – 11689Ig-like 1
Domain121 – 20585Ig-like 2
Domain212 – 30291Ig-like 3
Domain312 – 450139FZ
Domain574 – 855282Protein kinase
Nucleotide binding580 – 5889ATP By similarity

Sites

Active site7241Proton acceptor By similarity
Binding site6081ATP By similarity

Amino acid modifications

Modified residue5531Phosphotyrosine; by autocatalysis By similarity
Modified residue6801Phosphoserine; by CK2 By similarity
Modified residue6971Phosphoserine; by CK2 By similarity
Modified residue7541Phosphotyrosine; by autocatalysis Ref.5
Glycosylation2221N-linked (GlcNAc...) Potential
Glycosylation3381N-linked (GlcNAc...) Ref.8
Glycosylation4591N-linked (GlcNAc...) Potential
Disulfide bond49 ↔ 99 Ref.7 Ref.8
Disulfide bond98 ↔ 112 Ref.7 Ref.8
Disulfide bond142 ↔ 190 Ref.7 Ref.8
Disulfide bond233 ↔ 282 By similarity
Disulfide bond317 ↔ 382 Ref.7 Ref.8
Disulfide bond325 ↔ 375 Ref.7 Ref.8
Disulfide bond366 ↔ 406 Ref.7 Ref.8
Disulfide bond394 ↔ 447 Ref.7 Ref.8
Disulfide bond398 ↔ 434 Ref.7 Ref.8

Experimental info

Mutagenesis481M → R: Strongly reduced agrin-dependent activation and autophosphorylation. Ref.7
Mutagenesis831L → R: Abolishes agrin-dependent activation and autophosphorylation. Ref.7
Mutagenesis961I → A: Abolishes agrin-dependent activation and autophosphorylation. Ref.7

Secondary structure

......................................................................................................................... 868
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q62838 [UniParc].

Last modified November 1, 1996. Version 1.
Checksum: C146B4E74EE25B24

FASTA86896,822
        10         20         30         40         50         60 
MRELVNIPLL QMLTLVAFSG TEKLPKAPVI TTPLETVDAL VEEVATFMCA VESYPQPEIS 

        70         80         90        100        110        120 
WTRNKILIKL FDTRYSIREN GQLLTILSVE DSDDGIYCCT ANNGVGGAVE SCGALQVKMK 

       130        140        150        160        170        180 
PKITRPPINV KIIEGLKAVL PCTTMGNPKP SVSWIKGDSA LRENSRIAVL ESGSLRIHNV 

       190        200        210        220        230        240 
QKEDAGQYRC VAKNSLGTAY SKLVKLEVEV FARILRAPES HNVTFGSFVT LRCTAIGMPV 

       250        260        270        280        290        300 
PTISWIENGN AVSSGSIQEN VKDRVIDSRL QLFITKPGLY TCIATNKHGE KFSTAKAAAT 

       310        320        330        340        350        360 
VSIAEWSKSQ KESKGYCAQY RGEVCDAVLV KDSLVFFNTS YPDPEEAQEL LIHTAWNELK 

       370        380        390        400        410        420 
AVSPLCRPAA EALLCNHLFQ ECSPGVLPTP MPICREYCLA VKELFCAKEW LAMEGKTHRG 

       430        440        450        460        470        480 
LYRSGMHFLP VPECSKLPSM HQDPTACTRL PYLDYKKENI TTFPSITSSK PSVDIPNLPA 

       490        500        510        520        530        540 
STSSFAVSPA YSMTVIISIM SCFAVFALLT ITTLYCCRRR REWKNKKRES AAVTLTTLPS 

       550        560        570        580        590        600 
ELLLDRLHPN PMYQRMPLLL NPKLLSLEYP RNNIEYVRDI GEGAFGRVFQ ARAPGLLPYE 

       610        620        630        640        650        660 
PFTMVAVKML KEEASADMQA DFQREAALMA EFDNPNIVKL LGVCAVGKPM CLLFEYMAYG 

       670        680        690        700        710        720 
DLNEFLRSMS PHTVCSLSHS DLSTRARVSS PGPPPLSCAE QLCIARQVAA GMAYLSERKF 

       730        740        750        760        770        780 
VHRDLATRNC LVGENMVVKI ADFGLSRNIY SADYYKADGN DAIPIRWMPP ESIFYNRYTT 

       790        800        810        820        830        840 
ESDVWAYGVV LWEIFSYGLQ PYYGMAHEEV IYYVRDGNIL ACPENCPLEL YNLMRLCWSK 

       850        860 
LPADRPSFCS IHRILQRMCE RAEGTVGV 

« Hide

References

[1]"Receptor tyrosine kinase specific for the skeletal muscle lineage: expression in embryonic muscle, at the neuromuscular junction, and after injury."
Valenzuela D.M., Stitt T.N., DiStefano P.S., Rojas E., Mattsson K., Compton D.L., Nunez L., Park J.S., Stark J.L., Gies D.R., Thomas S., LeBeau M.M., Fernald A.A., Copeland N.G., Jenkins N.A., Burden S.J., Glass D.J., Yancopoulos G.D.
Neuron 15:573-584(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, INDUCTION BY DENERVATION.
Tissue: Muscle.
[2]"MuSK expressed in the brain mediates cholinergic responses, synaptic plasticity, and memory formation."
Garcia-Osta A., Tsokas P., Pollonini G., Landau E.M., Blitzer R., Alberini C.M.
J. Neurosci. 26:7919-7932(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN MEMORY FORMATION.
[3]"Lrp4 is a receptor for Agrin and forms a complex with MuSK."
Kim N., Stiegler A.L., Cameron T.O., Hallock P.T., Gomez A.M., Huang J.H., Hubbard S.R., Dustin M.L., Burden S.J.
Cell 135:334-342(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH LRP4.
[4]"A mammalian homolog of Drosophila tumorous imaginal discs, Tid1, mediates agrin signaling at the neuromuscular junction."
Linnoila J., Wang Y., Yao Y., Wang Z.Z.
Neuron 60:625-641(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH DNAJA3.
[5]"The cytoplasmic adaptor protein Dok7 activates the receptor tyrosine kinase MuSK via dimerization."
Bergamin E., Hallock P.T., Burden S.J., Hubbard S.R.
Mol. Cell 39:100-109(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH DOK7, ENZYME REGULATION, PHOSPHORYLATION AT TYR-754.
[6]"Crystal structure of the MuSK tyrosine kinase: insights into receptor autoregulation."
Till J.H., Becerra M., Watty A., Lu Y., Ma Y., Neubert T.A., Burden S.J., Hubbard S.R.
Structure 10:1187-1196(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.05 ANGSTROMS) OF 560-860.
[7]"Crystal structure of the agrin-responsive immunoglobulin-like domains 1 and 2 of the receptor tyrosine kinase MuSK."
Stiegler A.L., Burden S.J., Hubbard S.R.
J. Mol. Biol. 364:424-433(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.21 ANGSTROMS) OF 22-212, FUNCTION, PHOSPHORYLATION, SUBUNIT, SUBCELLULAR LOCATION, MUTAGENESIS OF MET-48; LEU-83 AND ILE-96, DISULFIDE BONDS.
[8]"Crystal structure of the frizzled-like cysteine-rich domain of the receptor tyrosine kinase MuSK."
Stiegler A.L., Burden S.J., Hubbard S.R.
J. Mol. Biol. 393:1-9(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 313-494, SUBUNIT, DISULFIDE BONDS, GLYCOSYLATION AT ASN-338.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U34985 mRNA. Translation: AAA90956.1.
RefSeqNP_112323.1. NM_031061.1.
UniGeneRn.10210.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1LUFX-ray2.05A529-868[»]
2IEPX-ray2.21A/B22-212[»]
3HKLX-ray2.10A/B313-494[»]
ProteinModelPortalQ62838.
SMRQ62838. Positions 25-211, 560-860.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

IntActQ62838. 7 interactions.
STRING10116.ENSRNOP00000056324.

PTM databases

PhosphoSiteQ62838.

Proteomic databases

PRIDEQ62838.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

GeneID81725.
KEGGrno:81725.
UCSCRGD:3211. rat.

Organism-specific databases

CTD4593.
RGD3211. Musk.

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000044461.
HOVERGENHBG052539.
KOK05129.

Gene expression databases

GenevestigatorQ62838.

Family and domain databases

Gene3D1.10.2000.10. 1 hit.
2.60.40.10. 3 hits.
InterProIPR020067. Frizzled_dom.
IPR007110. Ig-like_dom.
IPR013783. Ig-like_fold.
IPR013098. Ig_I-set.
IPR003598. Ig_sub2.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR008266. Tyr_kinase_AS.
IPR020635. Tyr_kinase_cat_dom.
[Graphical view]
PfamPF01392. Fz. 1 hit.
PF07679. I-set. 3 hits.
PF07714. Pkinase_Tyr. 1 hit.
[Graphical view]
PRINTSPR00109. TYRKINASE.
SMARTSM00408. IGc2. 3 hits.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS50038. FZ. 1 hit.
PS50835. IG_LIKE. 3 hits.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceQ62838.
NextBio615376.
PROQ62838.

Entry information

Entry nameMUSK_RAT
AccessionPrimary (citable) accession number: Q62838
Entry history
Integrated into UniProtKB/Swiss-Prot: July 19, 2004
Last sequence update: November 1, 1996
Last modified: April 16, 2014
This is version 121 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references