AiPD: Autoinhibited Protein Database

F8W3R9

Gene name	alk
Protein name	ALK tyrosine kinase receptor
Names	EC 2.7.10.1 , Anaplastic lymphoma kinase 2 , alk-2 , Anaplastic lymphoma kinase homolog
Species	Danio rerio (Zebrafish) (Brachydanio rerio)
KEGG Pathway
EC number	2.7.10.1: Protein-tyrosine kinases
Protein Class

Descriptions

ALK is a receptor tyrosine kinase involved in the development of several human cancers. Its autoinhibition is mediated by an intramolecular interaction between β-sheet (β1' and β2') and DFG helix in an activation loop, which occludes the substrate binding site. The activation loop contains phosphorylation sites, which need to be phosphorylated for ALK activation.

Autoinhibitory domains (AIDs)

1093-1100 (β1'-sheet and β2'-sheet) SS

Target domain	1113-1389 (Protein kinase domain)
Relief mechanism	PTM
Assay

AID

1093-1100 (β1'-sheet and β2'-sheet)

Target domain

1113-1389 (Protein kinase domain)

Relief mechanism

PTM (Phosphorylation within the activation loop)

Assay

Accessory elements

1266-1291 (Activation loop from InterPro)

Target domain	1113-1380 (Tyrosine-protein kinase, catalytic domain)
Relief mechanism
Assay

References

Bossi RT et al. (2010) "Crystal structures of anaplastic lymphoma kinase in complex with ATP competitive inhibitors", Biochemistry, 49, 6813-25

Donella-Deana A et al. (2005) "Unique substrate specificity of anaplastic lymphoma kinase (ALK): development of phosphoacceptor peptides for the assay of ALK activity", Biochemistry, 44, 8533-42

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

Tu CH et al. (2016) "Pyrazolylamine Derivatives Reveal the Conformational Switching between Type I and Type II Binding Modes of Anaplastic Lymphoma Kinase (ALK)", Journal of medicinal chemistry, 59, 3906-19

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,

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

0 structures for F8W3R9

Entry ID	Method	Resolution	Chain	Position	Source

No variants for F8W3R9

Variant ID(s)	Position	Change	Description	Diseaes Association	Provenance
No variants for F8W3R9

No associated diseases with F8W3R9

8 regional properties for F8W3R9

Type	Name	Position	InterPro Accession
domain	Protein kinase domain	1113 - 1389	IPR000719
domain	MAM domain	486 - 644	IPR000998
domain	Serine-threonine/tyrosine-protein kinase, catalytic domain	1114 - 1379	IPR001245
conserved_site	Tyrosine-protein kinase, receptor class II, conserved site	1273 - 1281	IPR002011
repeat	Low-density lipoprotein (LDL) receptor class A repeat	443 - 481	IPR002172
active_site	Tyrosine-protein kinase, active site	1242 - 1254	IPR008266
binding_site	Protein kinase, ATP binding site	1119 - 1147	IPR017441
domain	Tyrosine-protein kinase, catalytic domain	1113 - 1380	IPR020635

Functions

		Description
EC Number	2.7.10.1	Protein-tyrosine kinases
Subcellular Localization	Cell membrane ; Single-pass type I membrane protein
PANTHER Family
PANTHER Subfamily
PANTHER Protein Class
PANTHER Pathway Category	No pathway information available

2 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.
receptor complex	Any protein complex that undergoes combination with a hormone, neurotransmitter, drug or intracellular messenger to initiate a change in cell function.

2 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

6 GO annotations of biological process

Name	Definition
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 MAPK cascade	Any process that activates or increases the frequency, rate or extent of signal transduction mediated by the MAPK cascade.
positive regulation of neurogenesis	Any process that activates or increases the frequency, rate or extent of neurogenesis, the generation of cells within the nervous system.
regulation of cell population proliferation	Any process that modulates the frequency, rate or extent of cell proliferation.
regulation of neuron differentiation	Any process that modulates the frequency, rate or extent of neuron differentiation.
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.

17 homologous proteins in AiPD

UniProt AC	Gene Name	Protein Name	Species	Evidence Code
Q769I5	MET	Hepatocyte growth factor receptor	Bos taurus (Bovine)	PR
A0M8S8	MET	Hepatocyte growth factor receptor	Felis catus (Cat) (Felis silvestris catus)	PR
P29376	LTK	Leukocyte tyrosine kinase receptor	Homo sapiens (Human)	SS
Q04912	MST1R	Macrophage-stimulating protein receptor	Homo sapiens (Human)	EV
P08581	MET	Hepatocyte growth factor receptor	Homo sapiens (Human)	EV
P14616	INSRR	Insulin receptor-related protein	Homo sapiens (Human)	SS
P08922	ROS1	Proto-oncogene tyrosine-protein kinase ROS	Homo sapiens (Human)	SS
Q9UM73	ALK	ALK tyrosine kinase receptor	Homo sapiens (Human)	EV
Q9WTL4	Insrr	Insulin receptor-related protein	Mus musculus (Mouse)	SS
Q62190	Mst1r	Macrophage-stimulating protein receptor	Mus musculus (Mouse)	SS
P97793	Alk	ALK tyrosine kinase receptor	Mus musculus (Mouse)	SS
P16056	Met	Hepatocyte growth factor receptor	Mus musculus (Mouse)	PR
P97523	Met	Hepatocyte growth factor receptor	Rattus norvegicus (Rat)	PR
Q64716	Insrr	Insulin receptor-related protein	Rattus norvegicus (Rat)	SS
Q8I7I5	rol-3	Protein roller-3	Caenorhabditis elegans	PR
H2KZU7	svh-2	Tyrosine-protein kinase receptor svh-2	Caenorhabditis elegans	SS
F1QVU0	ltk	Tyrosine-protein kinase receptor	Danio rerio (Zebrafish) (Brachydanio rerio)	SS

10	20	30	40	50	60
MIARILYFFL	WSAAFLPELQ	CASQRTADAL	TTFPTSAFIN	GTDRKDSNQT	STSRIKRKTL
70	80	90	100	110	120
SVDFAVPSLL	RYYLALFIKR	PLNGDCLSFN	GCYTVRANLL	MRCVPLQKTI	AGLLDAKLAA
130	140	150	160	170	180
MNVNRSSTGQ	LPYRQKRPVP	KVLNLGLTSA	SRKSNQVVVE	VGEEMVKTGC	GGLHVYEDAP
190	200	210	220	230	240
VVFLEMDLTR	ILEWWLGAEG	GRLRVRLMPE	RKVQVPGKED	KYSAAIRASD	ARLFIQIASS
250	260	270	280	290	300
ERPSSTISRN	PTVAPKYWNF	SWIAEDELTF	PEDPVSTSDC	TSKAKSCDRR	PDGYYPEFAW
310	320	330	340	350	360
SLTSAEDSWA	IDQTMVKTKA	SSQGWEEGRF	LTVNSSALTG	PWVLSPWFRA	AHRPCGLDIT
370	380	390	400	410	420
VFLHPRQSGR	YTVWLIERDK	PPLALLTTEH	PHVIGWAVVH	LSLAARSKPF	RISSSYSQPG
430	440	450	460	470	480
EIETATYDPR	YSTNCTTRSS	QNVTLRGRYH	CRGGREINVS	QLCDFSIDCP	QGDDEGEHCR
490	500	510	520	530	540
QFLNGSYCSF	GREDCGWQPV	QGRGPQWRAH	PSIPQSLRSS	CPSPGALLAI	DSQPKGQRGS
550	560	570	580	590	600
AQVRSPLFFY	PLRNAPCMVK	FWVCGSSNGA	LSLWITENST	GPEGQRSLWN	STSEANMGKG
610	620	630	640	650	660
WKLITLPLFG	LVDLFYLQFS	ADISSSSGIA	FAVDNFTLSM	ECFLETNGEF	PPVAPISPTQ
670	680	690	700	710	720
ALFTQSNENI	KTTTTLYGGP	GASTESVKWI	FHTCGATGQD	GPTPTQCSNS	YRNTNVNVTV
730	740	750	760	770	780
GTKGPFKGIQ	MWQVPETRKY	RITAYGAAGG	RSVLAVHKSH	GVYMTGDFLL	QKDELLYILV
790	800	810	820	830	840
GQEGEDACPN	MVPTMDRICR	EQQGPSINKT	QLKGGGGGGG	GGTYVFKVVN	GVHIPLLIAA
850	860	870	880	890	900
GGGGRGYSSQ	SETPEEVMDR	DPSIPGRNGK	SGTAGGGGGW	NDSAPVPQGG	RPLILGGQGG
910	920	930	940	950	960
EPCQAMGWKT	RGGFGGGGGA	CTAGGGGGGY	RGGSAWHDND	PRKDGDDGTS	YISPDGEMYL
970	980	990	1000	1010	1020
EPLKGMEGNG	EVIINPVQNC	SHCESGDCHE	TSEGMVCYCD	EELTLAPDGV	SCINSTELPL
1030	1040	1050	1060	1070	1080
LPAQPSLSHL	ALGLSVGTSA	LIAALLLAVS	GVMIMYRRKH	TELQSIQLEL	QSPDCKLSKL
1090	1100	1110	1120	1130	1140
RASTIMTDYN	PNYCFGGKTA	SVNDLKEVPR	RNISLTRGLG	HGAFGEVYEG	LAVGIPGEPS
1150	1160	1170	1180	1190	1200
PMQVAVKTLP	EVCSEQDELD	FLMEALIISK	FSHQNIVRCI	GVSLQALPHF	ILLELMAGGD
1210	1220	1230	1240	1250	1260
LKSFLRETRP	RLEHPSSLTM	VDLLNIARDI	ARGCQYLEEN	QFIHRDIAAR	NCLLTCKGPG
1270	1280	1290	1300	1310	1320
RVAKIGDFGM	ARDIYRASYY	RKGGRAMLPV	KWMPPEAFME	GIFTSKTDTW	SFGVLLWEIF
1330	1340	1350	1360	1370	1380
SLGYMPYPSR	SNQEVLEFVT	NGGRMDPPKN	CPGPVYRIMT	QSWQHQPEDR	PNFSTILERI
1390	1400	1410	1420	1430	1440
DYCLQDPDVV	NVPLPVEYGP	IPEEEERVPM	RPEDPSAPSL	LVSPQGTEDV	PSATHSAQSK
1450	1460	1470	1480	1490	1500
KDGEAIHMAN	LSTDSKLPPV	PPSQPHPHHH	LQTPVVTAPV	PASKPSSTTS	NAQDGGHVNL
1510	1520	1530	1540	1550	1560
GFMQAHSSEK	ESRNRKPTNL	WNPTYGSWFL	QQQQKRQQVQ	AQRQTSGPRI	PGEGQEQVGR
1570	1580	1590	1600	1610	1620
TVTVAEALGL	QQQHKQQQYQ	QQLQRQQQQQ	QQQQQQQGLC	RPLLPPPPPP	APTPLLLDSA
1630	1640	1650	1660	1670	1680
TLAPVPLYRL	RRFPCGNIGY	GYQEQGLPME	PMQGPQLPPP	HPGQQRPISL	TRASGPEDSR
1690	1700
PLLVTMGTVQ	DSRLPKMEGH	NATVL