AiPD: Autoinhibited Protein Database

Q8AXY6

Gene name	MUSK
Protein name	Muscle, skeletal receptor tyrosine protein kinase
Names	EC 2.7.10.1 , Muscle-specific tyrosine protein kinase receptor , MuSK , Muscle-specific kinase receptor
Species	Gallus gallus (Chicken)
KEGG Pathway	gga:373897
EC number	2.7.10.1: Protein-tyrosine kinases
Protein Class

Descriptions

Muscle, skeletal receptor tyrosine-protein kinase (MuSK) RTK(receptor tyrosine kinase) that is expressed exclusively in muscle cells, and is essential for the formation of neuromuscular synapses because of its key role in clustering acetylcholine receptors. Mutation of the MUSK juxtamembrane Tyr residue results in the loss of ligand (agrin)-stimulated receptor autophosphorylation in muscle cells. However, the soluble cytoplasmic domain of MUSK bearing a Tyr553Phe substitution undergoes activation-segment autophosphorylation and kinase activation in vitro. MUSK is subject to strong activation-segment autoinhibition.

Autoinhibitory domains (AIDs)

614-649 (Juxtamembrane region) SS

Target domain	655-934 (Protein kinase domain)
Relief mechanism	PTM
Assay

AID

614-649 (Juxtamembrane region)

Target domain

655-934 (Protein kinase domain)

Relief mechanism

PTM (Autophosphorylation in the activation loop)

Assay

700-712 (αC helix) SS

Target domain	655-934 (Protein kinase domain)
Relief mechanism	Others
Assay

AID

700-712 (αC helix)

Target domain

655-934 (Protein kinase domain)

Relief mechanism

Others (Dissociation of DLG motif within the activation loop from αC helix)

Assay

Accessory elements

820-845 (Activation loop from InterPro)

Target domain	655-934 (Protein kinase domain)
Relief mechanism
Assay

References

Hubbard SR (2004) "Juxtamembrane autoinhibition in receptor tyrosine kinases", Nature reviews. Molecular cell biology, 5, 464-71

Artim SC et al. (2012) "Assessing the range of kinase autoinhibition mechanisms in the insulin receptor family", The Biochemical journal, 448, 213-20

Uchikawa E et al. (2019) "Activation mechanism of the insulin receptor revealed by cryo-EM structure of the fully liganded receptor-ligand complex", eLife, 8,

Nielsen J et al. (2022) "Structural Investigations of Full-Length Insulin Receptor Dynamics and Signalling", Journal of molecular biology, 434, 167458

Chen YS et al. (2021) "Insertion of a synthetic switch into insulin provides metabolite-dependent regulation of hormone-receptor activation", Proceedings of the National Academy of Sciences of the United States of America, 118,

Craddock BP et al. (2007) "Autoinhibition of the insulin-like growth factor I receptor by the juxtamembrane region", FEBS letters, 581, 3235-40

Huang X et al. (2009) "Structural insights into the inhibited states of the Mer receptor tyrosine kinase", Journal of structural biology, 165, 88-96

Autoinhibited structure

Activated structure

1 structures for Q8AXY6

Entry ID	Method	Resolution	Chain	Position	Source
AF-Q8AXY6-F1	Predicted				AlphaFoldDB

No variants for Q8AXY6

Variant ID(s)	Position	Change	Description	Diseaes Association	Provenance
No variants for Q8AXY6

No associated diseases with Q8AXY6

19 regional properties for Q8AXY6

Type	Name	Position	InterPro Accession
domain	Kringle	462 - 545	IPR000001
domain	Protein kinase domain	655 - 934	IPR000719
domain	Serine-threonine/tyrosine-protein kinase, catalytic domain	656 - 934	IPR001245
domain	Immunoglobulin subtype 2	40 - 106	IPR003598-1
domain	Immunoglobulin subtype 2	133 - 197	IPR003598-2
domain	Immunoglobulin subtype 2	224 - 289	IPR003598-3
domain	Immunoglobulin subtype	34 - 118	IPR003599-1
domain	Immunoglobulin subtype	127 - 209	IPR003599-2
domain	Immunoglobulin subtype	218 - 304	IPR003599-3
domain	Immunoglobulin-like domain	28 - 116	IPR007110-1
domain	Immunoglobulin-like domain	121 - 207	IPR007110-2
domain	Immunoglobulin-like domain	212 - 302	IPR007110-3
active_site	Tyrosine-protein kinase, active site	799 - 811	IPR008266
domain	Immunoglobulin I-set	29 - 112	IPR013098-1
domain	Immunoglobulin I-set	121 - 201	IPR013098-2
binding_site	Protein kinase, ATP binding site	661 - 689	IPR017441
conserved_site	Kringle, conserved site	513 - 526	IPR018056
domain	Frizzled domain	312 - 451	IPR020067
domain	Tyrosine-protein kinase, catalytic domain	655 - 934	IPR020635

Functions

		Description
EC Number	2.7.10.1	Protein-tyrosine kinases
Subcellular Localization	Postsynaptic cell membrane ; Single-pass type I membrane protein	Localizes to the postsynaptic cell membrane of the neuromuscular junction
PANTHER Family
PANTHER Subfamily
PANTHER Protein Class
PANTHER Pathway Category	No pathway information available

3 GO annotations of cellular component

Name	Definition
plasma membrane	The membrane surrounding a cell that separates the cell from its external environment. It consists of a phospholipid bilayer and associated proteins.
postsynaptic membrane	A specialized area of membrane facing the presynaptic membrane on the tip of the nerve ending and separated from it by a minute cleft (the synaptic cleft). Neurotransmitters cross the synaptic cleft and transmit the signal to the postsynaptic membrane.
receptor complex	Any protein complex that undergoes combination with a hormone, neurotransmitter, drug or intracellular messenger to initiate a change in cell function.

3 GO annotations of molecular function

Name	Definition
ATP binding	Binding to ATP, adenosine 5'-triphosphate, a universally important coenzyme and enzyme regulator.
transmembrane receptor protein tyrosine kinase activity	Combining with a signal and transmitting the signal from one side of the membrane to the other to initiate a change in cell activity by catalysis of the reaction
Wnt-protein binding	Binding to a Wnt-protein, a secreted growth factor involved in signaling.

5 GO annotations of biological process

Name	Definition
cell differentiation	The cellular developmental process in which a relatively unspecialized cell, e.g. embryonic or regenerative cell, acquires specialized structural and/or functional features that characterize a specific cell. Differentiation includes the processes involved in commitment of a cell to a specific fate and its subsequent development to the mature state.
phosphorylation	The process of introducing a phosphate group into a molecule, usually with the formation of a phosphoric ester, a phosphoric anhydride or a phosphoric amide.
positive regulation of neuron projection development	Any process that increases the rate, frequency or extent of neuron projection development. Neuron projection development is the process whose specific outcome is the progression of a neuron projection over time, from its formation to the mature structure. A neuron projection is any process extending from a neural cell, such as axons or dendrites (collectively called neurites).
regulation of synaptic assembly at neuromuscular junction	Any process that modulates the frequency, rate or extent of synaptic assembly at neuromuscular junctions.
transmembrane receptor protein tyrosine kinase signaling pathway	The series of molecular signals initiated by an extracellular ligand binding to a receptor on the surface of the target cell where the receptor possesses tyrosine kinase activity, and ending with the regulation of a downstream cellular process, e.g. transcription.

53 homologous proteins in AiPD

UniProt AC	Gene Name	Protein Name	Species	Evidence Code
Q91044	NTRK3	NT-3 growth factor receptor	Gallus gallus (Chicken)	SS
Q5F3X2	DDR1	receptor protein-tyrosine kinase	Gallus gallus (Chicken)	SS
Q91987	NTRK2	BDNF/NT-3 growth factors receptor	Gallus gallus (Chicken)	SS
Q8QHL3	FLT1	Vascular endothelial growth factor receptor 1	Gallus gallus (Chicken)	SS
P21804	FGFR1	Fibroblast growth factor receptor 1	Gallus gallus (Chicken)	SS
P18461	FGFR2	Fibroblast growth factor receptor 2	Gallus gallus (Chicken)	SS
P18460	FGFR3	Fibroblast growth factor receptor 3	Gallus gallus (Chicken)	SS
Q98949	TYRO3	Tyrosine-protein kinase receptor TYRO3	Gallus gallus (Chicken)	PR
Q08156	KIT	Mast/stem cell growth factor receptor Kit	Gallus gallus (Chicken)	SS
Q91009	NTRK1	High affinity nerve growth factor receptor	Gallus gallus (Chicken)	SS
Q07494	EPHB1	Ephrin type-B receptor 1	Gallus gallus (Chicken)	SS
Q9PUF6	PDGFRA	Platelet-derived growth factor receptor alpha	Gallus gallus (Chicken)	SS
Q5IS37	NTRK3	NT-3 growth factor receptor	Pan troglodytes (Chimpanzee)	SS
Q24488	Ror	Tyrosine-protein kinase transmembrane receptor Ror	Drosophila melanogaster (Fruit fly)	SS
Q9V6K3	Nrk	Tyrosine-protein kinase transmembrane receptor Ror2	Drosophila melanogaster (Fruit fly)	SS
Q16620	NTRK2	BDNF/NT-3 growth factors receptor	Homo sapiens (Human)	EV
Q16288	NTRK3	NT-3 growth factor receptor	Homo sapiens (Human)	SS
Q01973	ROR1	Inactive tyrosine-protein kinase transmembrane receptor ROR1	Homo sapiens (Human)	PR
Q01974	ROR2	Tyrosine-protein kinase transmembrane receptor ROR2	Homo sapiens (Human)	EV
P04629	NTRK1	High affinity nerve growth factor receptor	Homo sapiens (Human)	EV
O15146	MUSK	Muscle, skeletal receptor tyrosine-protein kinase	Homo sapiens (Human)	EV
Q9Z138	Ror2	Tyrosine-protein kinase transmembrane receptor ROR2	Mus musculus (Mouse)	SS
Q3UFB7	Ntrk1	High affinity nerve growth factor receptor	Mus musculus (Mouse)	SS
Q6VNS1	Ntrk3	NT-3 growth factor receptor	Mus musculus (Mouse)	SS
Q9Z139	Ror1	Inactive tyrosine-protein kinase transmembrane receptor ROR1	Mus musculus (Mouse)	PR
P15209	Ntrk2	BDNF/NT-3 growth factors receptor	Mus musculus (Mouse)	SS
Q61006	Musk	Muscle, skeletal receptor tyrosine-protein kinase	Mus musculus (Mouse)	SS
P24786	NTRK3	NT-3 growth factor receptor	Sus scrofa (Pig)	SS
P35739	Ntrk1	High affinity nerve growth factor receptor	Rattus norvegicus (Rat)	SS
Q03351	Ntrk3	NT-3 growth factor receptor	Rattus norvegicus (Rat)	SS
Q63604	Ntrk2	BDNF/NT-3 growth factors receptor	Rattus norvegicus (Rat)	SS
Q62838	Musk	Muscle, skeletal receptor tyrosine protein kinase	Rattus norvegicus (Rat)	SS
G5EGK5	cam-1	Tyrosine-protein kinase receptor cam-1	Caenorhabditis elegans	SS
O64770	At1g61490	G-type lectin S-receptor-like serine/threonine-protein kinase At1g61490	Arabidopsis thaliana (Mouse-ear cress)	SS
O64783	At1g61370	G-type lectin S-receptor-like serine/threonine-protein kinase At1g61370	Arabidopsis thaliana (Mouse-ear cress)	SS
O81833	SD11	G-type lectin S-receptor-like serine/threonine-protein kinase SD1-1	Arabidopsis thaliana (Mouse-ear cress)	PR
Q8RWZ5	SD25	G-type lectin S-receptor-like serine/threonine-protein kinase SD2-5	Arabidopsis thaliana (Mouse-ear cress)	PR
Q9FNE1	CRK42	Cysteine-rich receptor-like protein kinase 42	Arabidopsis thaliana (Mouse-ear cress)	PR
Q9LPZ9	SD113	G-type lectin S-receptor-like serine/threonine-protein kinase SD1-13	Arabidopsis thaliana (Mouse-ear cress)	SS
Q9SXB5	At1g11303	G-type lectin S-receptor-like serine/threonine-protein kinase At1g11303	Arabidopsis thaliana (Mouse-ear cress)	PR
Q9SYA0	At1g61500	G-type lectin S-receptor-like serine/threonine-protein kinase At1g61500	Arabidopsis thaliana (Mouse-ear cress)	SS
O64780	At1g61400	G-type lectin S-receptor-like serine/threonine-protein kinase At1g61400	Arabidopsis thaliana (Mouse-ear cress)	SS
O64776	At1g61440	G-type lectin S-receptor-like serine/threonine-protein kinase At1g61440	Arabidopsis thaliana (Mouse-ear cress)	SS
O64778	At1g61420	G-type lectin S-receptor-like serine/threonine-protein kinase At1g61420	Arabidopsis thaliana (Mouse-ear cress)	SS
Q9SY95	At1g61550	G-type lectin S-receptor-like serine/threonine-protein kinase At1g61550	Arabidopsis thaliana (Mouse-ear cress)	SS
O64774	At1g61460	G-type lectin S-receptor-like serine/threonine-protein kinase At1g61460	Arabidopsis thaliana (Mouse-ear cress)	PR
O64782	SD129	G-type lectin S-receptor-like serine/threonine-protein kinase SD1-29	Arabidopsis thaliana (Mouse-ear cress)	SS
Q9SXB4	At1g11300	G-type lectin S-receptor-like serine/threonine-protein kinase At1g11300	Arabidopsis thaliana (Mouse-ear cress)	PR
O64477	At2g19130	G-type lectin S-receptor-like serine/threonine-protein kinase At2g19130	Arabidopsis thaliana (Mouse-ear cress)	SS
O64793	At1g67520	G-type lectin S-receptor-like serine/threonine-protein kinase At1g67520	Arabidopsis thaliana (Mouse-ear cress)	PR
Q9SXB8	At1g11330	G-type lectin S-receptor-like serine/threonine-protein kinase At1g11330	Arabidopsis thaliana (Mouse-ear cress)	PR
O64784	At1g61360	G-type lectin S-receptor-like serine/threonine-protein kinase At1g61360	Arabidopsis thaliana (Mouse-ear cress)	SS
Q39203	SD22	G-type lectin S-receptor-like serine/threonine-protein kinase SD2-2	Arabidopsis thaliana (Mouse-ear cress)	SS

10	20	30	40	50	60
MRDLLVVPLG	HVLTLAALSL	AETLQKAPFI	STPLETVDAL	VEDVPKFVCV	VESYPEPEIT
70	80	90	100	110	120
WTRNSIPIRL	FDTRYSIQRN	GQLLTILSVE	DSDDGVYCCT	ADNGVGAAAQ	SCGALQVKMR
130	140	150	160	170	180
PKITRPPVNV	EIIEGLKAVL	PCTTMGNPKP	SVSWIKGETV	VKENARIAVL	DSGNLRIHNV
190	200	210	220	230	240
QREDAGQYRC	VAKNSLGSAY	SKPATVVVEV	FARILKAPES	QNITFGSMVT	LRCTAAGAPV
250	260	270	280	290	300
PTVTWLENGK	AVSAGSIAES	VKDRVVDSRL	QVYVTRPGLF	TCLATNKHSK	TFGAAKAAAT
310	320	330	340	350	360
ISVSEWSKLY	KGDAGYCSTY	RGEVCSAILS	RNALVFFNSS	YADPEETQEL	LVHTAWTELK
370	380	390	400	410	420
TVSSFCQPAA	ESLLCNYIFQ	ECKPSGVGPA	PKPICRENCL	AVKDLYCFKE	WLSMEENSQR
430	440	450	460	470	480
GIYKPGLMLL	ALPECNRLPS	LHQDPSACTH	IPFFDFKKEN	ITRTCYSGNG	QFYQGWANVT
490	500	510	520	530	540
ASGIPCQKWS	DQAPHLHRRT	PQVFPELSDA	ENYCRNPGGE	NERPWCYTKD	PSVTWEYCSV
550	560	570	580	590	600
SPCGDASLSL	GTRKPNGETQ	NLPPPPSYSP	TYSMNVIILI	ISSFALIVIL	GIITLVCCRR
610	620	630	640	650	660
RKQWKNKKRE	SETPTLTTLP	SELLLDRLHP	NPMYQRMPLL	LNPKLLSLEY	PRNNIEYVRD
670	680	690	700	710	720
IGEGAFGRVF	QARAPGLLPY	EPFTMVAVKM	LKEEASADMQ	ADFQREAALM	AEFDNPNIVK
730	740	750	760	770	780
LLGVCAVGKP	MCLLFEYMAY	GDLNEYLRDR	SPRNLCSLVQ	GGLEARACLL	NPLALCCTSQ
790	800	810	820	830	840
LCIAKQVAAG	MAYLSERKFV	HRDLATRNCL	VGENMVVKIA	DFGLSRNMYS	ADYYKANEND
850	860	870	880	890	900
AIPIRWMPPE	SIFYNRYTTE	SDVWAYGVVL	WEIFSYGMQP	YYGMAHEEVI	YYVRDGNILS
910	920	930	940
CPDNCPLELY	NLMRLCWSKL	PADRPSFASI	HRILERMYER	AVASPQV