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Protein

Muscle, skeletal receptor tyrosine protein kinase

Gene

Musk

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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 (PubMed:23326516). 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.3 Publications

Catalytic activityi

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

Cofactori

Mg2+By similarity

Enzyme regulationi

Positively regulated by CK2.By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei608ATPPROSITE-ProRule annotation1
Active sitei724Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi580 – 588ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • metal ion binding Source: UniProtKB-KW
  • protein kinase binding Source: RGD
  • protein tyrosine kinase activity Source: UniProtKB
  • transmembrane receptor protein tyrosine kinase activity Source: UniProtKB-EC

GO - Biological processi

  • cell differentiation Source: UniProtKB-KW
  • cochlea development Source: RGD
  • long-term synaptic potentiation Source: RGD
  • memory Source: RGD
  • negative regulation of gene expression Source: RGD
  • neuromuscular junction development Source: UniProtKB
  • positive regulation of gene expression Source: RGD
  • positive regulation of peptidyl-tyrosine phosphorylation Source: RGD
  • positive regulation of protein phosphorylation Source: RGD
  • positive regulation of synaptic growth at neuromuscular junction Source: RGD
  • positive regulation of synaptic transmission, cholinergic Source: RGD
  • protein autophosphorylation Source: RGD
  • receptor clustering Source: RGD
  • regulation of synaptic growth at neuromuscular junction Source: UniProtKB
  • response to axon injury Source: RGD
  • response to electrical stimulus Source: RGD
  • response to muscle activity Source: RGD
  • retina development in camera-type eye Source: RGD
Complete GO annotation...

Keywords - Molecular functioni

Developmental protein, Kinase, Muscle protein, Receptor, Transferase, Tyrosine-protein kinase

Keywords - Biological processi

Differentiation

Keywords - Ligandi

ATP-binding, Magnesium, Metal-binding, Nucleotide-binding

Names & Taxonomyi

Protein namesi
Recommended 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 namesi
Name:Musk
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Unplaced

Organism-specific databases

RGDi3211. Musk.

Subcellular locationi

  • Cell junctionsynapsepostsynaptic cell membrane 1 Publication; Single-pass type I membrane protein 1 Publication

  • Note: Localizes to the postsynaptic cell membrane of the neuromuscular junction.By similarityCurated

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini22 – 494ExtracellularSequence analysisAdd BLAST473
Transmembranei495 – 515HelicalSequence analysisAdd BLAST21
Topological domaini516 – 868CytoplasmicSequence analysisAdd BLAST353

GO - Cellular componenti

  • cell junction Source: UniProtKB-KW
  • cell projection Source: RGD
  • external side of plasma membrane Source: RGD
  • integral component of membrane Source: UniProtKB-KW
  • neuromuscular junction Source: RGD
  • plasma membrane Source: UniProtKB
  • postsynaptic membrane Source: UniProtKB-SubCell
Complete GO annotation...

Keywords - Cellular componenti

Cell junction, Cell membrane, Membrane, Postsynaptic cell membrane, Synapse

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi48M → R: Strongly reduced agrin-dependent activation and autophosphorylation. 1 Publication1
Mutagenesisi83L → R: Abolishes agrin-dependent activation and autophosphorylation. 1 Publication1
Mutagenesisi96I → A: Abolishes agrin-dependent activation and autophosphorylation. 1 Publication1
Mutagenesisi789V → M: Reduces interaction with DOK7. 1 Publication1
Mutagenesisi834M → V: Reduces LRP4- and AGRIN-dependent phosphorylation. Reduces DOK7-dependent phosphorylation. Reduces agrin-dependent AChR aggregation in neuromuscular junction. Reduces interaction with DOK7. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 21Sequence analysisAdd BLAST21
ChainiPRO_000002444822 – 868Muscle, skeletal receptor tyrosine protein kinaseAdd BLAST847

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi49 ↔ 99
Disulfide bondi98 ↔ 112
Disulfide bondi142 ↔ 190
Glycosylationi222N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi233 ↔ 282By similarity
Disulfide bondi317 ↔ 382
Disulfide bondi325 ↔ 375
Glycosylationi338N-linked (GlcNAc...)1 Publication1
Disulfide bondi366 ↔ 406
Disulfide bondi394 ↔ 447
Disulfide bondi398 ↔ 434
Glycosylationi459N-linked (GlcNAc...)Sequence analysis1
Modified residuei553Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei680Phosphoserine; by CK2By similarity1
Modified residuei697Phosphoserine; by CK2By similarity1
Modified residuei754Phosphotyrosine; by autocatalysis1 Publication1

Post-translational modificationi

Ubiquitinated by PDZRN3. Ubiquitination promotes endocytosis and lysosomal degradation (By similarity).By similarity
Phosphorylated (PubMed:23326516). Phosphorylation is induced by AGRIN in a LRP4-dependent manner (PubMed:23326516). Autophosphorylated. Autophosphorylation at Tyr-553 is required for interaction with DOK7 which in turn stimulates the phosphorylation and the activation of MUSK (By similarity).By similarity1 Publication
Neddylated.By similarity

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiQ62838.
PRIDEiQ62838.

PTM databases

iPTMnetiQ62838.
PhosphoSitePlusiQ62838.

Expressioni

Tissue specificityi

Muscle specific.1 Publication

Developmental stagei

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.1 Publication

Inductioni

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

Interactioni

Subunit structurei

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). Interacts with DOK7 (PubMed:23326516).By similarityCurated1 Publication

GO - Molecular functioni

  • protein kinase binding Source: RGD

Protein-protein interaction databases

IntActiQ62838. 7 interactors.
STRINGi10116.ENSRNOP00000041075.

Structurei

Secondary structure

1868
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi26 – 32Combined sources7
Beta strandi36 – 40Combined sources5
Beta strandi45 – 48Combined sources4
Beta strandi51 – 55Combined sources5
Beta strandi58 – 63Combined sources6
Beta strandi75 – 78Combined sources4
Helixi79 – 81Combined sources3
Beta strandi83 – 88Combined sources6
Helixi91 – 93Combined sources3
Beta strandi95 – 102Combined sources8
Beta strandi104 – 106Combined sources3
Beta strandi109 – 125Combined sources17
Beta strandi130 – 133Combined sources4
Beta strandi138 – 140Combined sources3
Beta strandi143 – 148Combined sources6
Beta strandi151 – 156Combined sources6
Beta strandi165 – 169Combined sources5
Beta strandi175 – 179Combined sources5
Helixi182 – 184Combined sources3
Beta strandi186 – 194Combined sources9
Beta strandi197 – 200Combined sources4
Beta strandi204 – 209Combined sources6
Beta strandi315 – 318Combined sources4
Beta strandi323 – 325Combined sources3
Turni326 – 328Combined sources3
Beta strandi335 – 338Combined sources4
Beta strandi341 – 343Combined sources3
Helixi344 – 359Combined sources16
Turni364 – 366Combined sources3
Helixi367 – 378Combined sources12
Beta strandi384 – 387Combined sources4
Helixi395 – 403Combined sources9
Turni404 – 409Combined sources6
Helixi410 – 424Combined sources15
Helixi434 – 436Combined sources3
Turni440 – 442Combined sources3
Beta strandi446 – 448Combined sources3
Turni451 – 453Combined sources3
Helixi562 – 566Combined sources5
Helixi571 – 573Combined sources3
Beta strandi575 – 582Combined sources8
Beta strandi587 – 594Combined sources8
Beta strandi600 – 609Combined sources10
Helixi616 – 630Combined sources15
Beta strandi640 – 644Combined sources5
Beta strandi646 – 649Combined sources4
Beta strandi651 – 655Combined sources5
Helixi662 – 668Combined sources7
Helixi698 – 717Combined sources20
Helixi727 – 729Combined sources3
Beta strandi730 – 732Combined sources3
Helixi734 – 736Combined sources3
Beta strandi738 – 740Combined sources3
Helixi746 – 749Combined sources4
Helixi751 – 753Combined sources3
Helixi765 – 767Combined sources3
Helixi770 – 775Combined sources6
Helixi780 – 795Combined sources16
Turni796 – 798Combined sources3
Turni801 – 804Combined sources4
Helixi807 – 815Combined sources9
Helixi828 – 837Combined sources10
Helixi842 – 844Combined sources3
Helixi848 – 857Combined sources10

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1LUFX-ray2.05A529-868[»]
2IEPX-ray2.21A/B22-212[»]
3HKLX-ray2.10A/B313-494[»]
ProteinModelPortaliQ62838.
SMRiQ62838.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ62838.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini28 – 116Ig-like 1Add BLAST89
Domaini121 – 205Ig-like 2Add BLAST85
Domaini212 – 302Ig-like 3Add BLAST91
Domaini312 – 450FZPROSITE-ProRule annotationAdd BLAST139
Domaini574 – 855Protein kinasePROSITE-ProRule annotationAdd BLAST282

Sequence similaritiesi

Belongs to the protein kinase superfamily. Tyr protein kinase family.PROSITE-ProRule annotation
Contains 1 FZ (frizzled) domain.PROSITE-ProRule annotation
Contains 1 protein kinase domain.PROSITE-ProRule annotation

Keywords - Domaini

Immunoglobulin domain, Repeat, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG1026. Eukaryota.
ENOG410YGKQ. LUCA.
HOGENOMiHOG000044461.
HOVERGENiHBG052539.
InParanoidiQ62838.
KOiK05129.

Family and domain databases

Gene3Di1.10.2000.10. 1 hit.
2.60.40.10. 3 hits.
InterProiIPR020067. Frizzled_dom.
IPR007110. Ig-like_dom.
IPR013783. Ig-like_fold.
IPR013098. Ig_I-set.
IPR003599. Ig_sub.
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]
PfamiPF01392. Fz. 1 hit.
PF07679. I-set. 3 hits.
PF07714. Pkinase_Tyr. 1 hit.
[Graphical view]
PRINTSiPR00109. TYRKINASE.
SMARTiSM00409. IG. 3 hits.
SM00408. IGc2. 3 hits.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMiSSF48726. SSF48726. 3 hits.
SSF56112. SSF56112. 1 hit.
PROSITEiPS50038. 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]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q62838-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MRELVNIPLL QMLTLVAFSG TEKLPKAPVI TTPLETVDAL VEEVATFMCA
60 70 80 90 100
VESYPQPEIS WTRNKILIKL FDTRYSIREN GQLLTILSVE DSDDGIYCCT
110 120 130 140 150
ANNGVGGAVE SCGALQVKMK PKITRPPINV KIIEGLKAVL PCTTMGNPKP
160 170 180 190 200
SVSWIKGDSA LRENSRIAVL ESGSLRIHNV QKEDAGQYRC VAKNSLGTAY
210 220 230 240 250
SKLVKLEVEV FARILRAPES HNVTFGSFVT LRCTAIGMPV PTISWIENGN
260 270 280 290 300
AVSSGSIQEN VKDRVIDSRL QLFITKPGLY TCIATNKHGE KFSTAKAAAT
310 320 330 340 350
VSIAEWSKSQ KESKGYCAQY RGEVCDAVLV KDSLVFFNTS YPDPEEAQEL
360 370 380 390 400
LIHTAWNELK AVSPLCRPAA EALLCNHLFQ ECSPGVLPTP MPICREYCLA
410 420 430 440 450
VKELFCAKEW LAMEGKTHRG LYRSGMHFLP VPECSKLPSM HQDPTACTRL
460 470 480 490 500
PYLDYKKENI TTFPSITSSK PSVDIPNLPA STSSFAVSPA YSMTVIISIM
510 520 530 540 550
SCFAVFALLT ITTLYCCRRR REWKNKKRES AAVTLTTLPS ELLLDRLHPN
560 570 580 590 600
PMYQRMPLLL NPKLLSLEYP RNNIEYVRDI GEGAFGRVFQ ARAPGLLPYE
610 620 630 640 650
PFTMVAVKML KEEASADMQA DFQREAALMA EFDNPNIVKL LGVCAVGKPM
660 670 680 690 700
CLLFEYMAYG DLNEFLRSMS PHTVCSLSHS DLSTRARVSS PGPPPLSCAE
710 720 730 740 750
QLCIARQVAA GMAYLSERKF VHRDLATRNC LVGENMVVKI ADFGLSRNIY
760 770 780 790 800
SADYYKADGN DAIPIRWMPP ESIFYNRYTT ESDVWAYGVV LWEIFSYGLQ
810 820 830 840 850
PYYGMAHEEV IYYVRDGNIL ACPENCPLEL YNLMRLCWSK LPADRPSFCS
860
IHRILQRMCE RAEGTVGV
Length:868
Mass (Da):96,822
Last modified:November 1, 1996 - v1
Checksum:iC146B4E74EE25B24
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U34985 mRNA. Translation: AAA90956.1.
RefSeqiNP_112323.1. NM_031061.1.
UniGeneiRn.10210.

Genome annotation databases

GeneIDi81725.
KEGGirno:81725.
UCSCiRGD:3211. rat.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U34985 mRNA. Translation: AAA90956.1.
RefSeqiNP_112323.1. NM_031061.1.
UniGeneiRn.10210.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1LUFX-ray2.05A529-868[»]
2IEPX-ray2.21A/B22-212[»]
3HKLX-ray2.10A/B313-494[»]
ProteinModelPortaliQ62838.
SMRiQ62838.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiQ62838. 7 interactors.
STRINGi10116.ENSRNOP00000041075.

PTM databases

iPTMnetiQ62838.
PhosphoSitePlusiQ62838.

Proteomic databases

PaxDbiQ62838.
PRIDEiQ62838.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi81725.
KEGGirno:81725.
UCSCiRGD:3211. rat.

Organism-specific databases

CTDi4593.
RGDi3211. Musk.

Phylogenomic databases

eggNOGiKOG1026. Eukaryota.
ENOG410YGKQ. LUCA.
HOGENOMiHOG000044461.
HOVERGENiHBG052539.
InParanoidiQ62838.
KOiK05129.

Miscellaneous databases

EvolutionaryTraceiQ62838.
PROiQ62838.

Family and domain databases

Gene3Di1.10.2000.10. 1 hit.
2.60.40.10. 3 hits.
InterProiIPR020067. Frizzled_dom.
IPR007110. Ig-like_dom.
IPR013783. Ig-like_fold.
IPR013098. Ig_I-set.
IPR003599. Ig_sub.
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]
PfamiPF01392. Fz. 1 hit.
PF07679. I-set. 3 hits.
PF07714. Pkinase_Tyr. 1 hit.
[Graphical view]
PRINTSiPR00109. TYRKINASE.
SMARTiSM00409. IG. 3 hits.
SM00408. IGc2. 3 hits.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMiSSF48726. SSF48726. 3 hits.
SSF56112. SSF56112. 1 hit.
PROSITEiPS50038. 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]
ProtoNetiSearch...

Entry informationi

Entry nameiMUSK_RAT
AccessioniPrimary (citable) accession number: Q62838
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 19, 2004
Last sequence update: November 1, 1996
Last modified: November 2, 2016
This is version 138 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  2. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.