O70405 (ULK1_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Serine/threonine-protein kinase ULK1
EC=2.7.11.1

Alternative name(s):
Serine/threonine-protein kinase Unc51.1
Unc-51-like kinase 1

Gene names

Name:

Ulk1

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	1051 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Serine/threonine-protein kinase involved in autophagy in response to starvation. Acts upstream of phosphatidylinositol 3-kinase PIK3C3 to regulate the formation of autophagophores, the precursors of autophagosomes. Part of regulatory feedback loops in autophagy: acts both as a downstream effector and negative regulator of mammalian target of rapamycin complex 1 (mTORC1) via interaction with RPTOR. Activated via phosphorylation by AMPK and also acts as a regulator of AMPK by mediating phosphorylation of AMPK subunits PRKAA1, PRKAB2 and PRKAG1, leading to negatively regulate AMPK activity. May phosphorylate ATG13/KIAA0652 and RPTOR; however such data need additional evidences. Plays a role early in neuronal differentiation and is required for granule cell axon formation. Ref.2 Ref.5 Ref.6 Ref.7 Ref.8
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Subunit structure	Interacts with GABARAP and GABARAPL2 By similarity. Interacts (via C-terminus) with ATG13 By similarity. Part of a complex consisting of ATG13, ATG101, ULK1 and RB1CC1. Associates with the mammalian target of rapamycin complex 1 (mTORC1) through an interaction with RPTOR; the association depends on nutrient conditions and is reduced during starvation By similarity. Interacts with FEZ1; SCOC interferes with FEZ1-binding By similarity. Interacts with TBC1D14 By similarity. Ref.5
Subcellular location	Cytoplasm › cytosol. Preautophagosomal structure. Note: Under starvation conditions, is localized to puncate structures primarily representing the isolation membrane that sequesters a portion of the cytoplasm resulting in the formation of an autophagosome. Ref.5
Post-translational modification	Autophosphorylated. Phosphorylated under nutrient-rich conditions; dephosphorylated during starvation or following treatment with rapamycin. In response to nutrient limitation, phosphorylated and activated by AMPK, leading to activate autophagy. Under nutrient sufficiency, phosphorylated by MTOR/mTOR, disrupting the interaction with AMPK and preventing activation of ULK1. Ref.5 Ref.7 Ref.8
Sequence similarities	Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. APG1/unc-51/ULK1 subfamily. Contains 1 protein kinase domain.

Ontologies

Keywords
Biological process	Autophagy
Cellular component	Cytoplasm
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	Ras protein signal transduction Inferred from direct assay PubMed 15014045. Source: MGI autophagic vacuole assembly Inferred from mutant phenotype Ref.5. Source: UniProtKB axon extension Inferred from mutant phenotype PubMed 17389358. Source: MGI cerebellar granule cell differentiation Inferred from mutant phenotype Ref.2. Source: MGI negative regulation of collateral sprouting Inferred from mutant phenotype PubMed 17389358. Source: MGI neuron projection regeneration Inferred from electronic annotation. Source: Compara positive regulation of autophagy Inferred from mutant phenotype Ref.7. Source: UniProtKB positive regulation of macroautophagy Inferred from electronic annotation. Source: Compara protein autophosphorylation Inferred from direct assay Ref.2Ref.1. Source: MGI protein localization Inferred from sequence or structural similarity. Source: UniProtKB radial glia guided migration of cerebellar granule cell Inferred from mutant phenotype Ref.2. Source: MGI receptor internalization Inferred from mutant phenotype PubMed 17389358. Source: MGI regulation of neurotrophin TRK receptor signaling pathway Inferred from mutant phenotype PubMed 17389358. Source: MGI
Cellular_component	ULK1-ATG13-FIP200 complex Inferred from physical interaction Ref.5. Source: UniProtKB autophagic vacuole Inferred from electronic annotation. Source: Compara cytoplasmic vesicle membrane Inferred from direct assay PubMed 15014045. Source: MGI cytosol Inferred from direct assay Ref.5. Source: UniProtKB neuron projection Inferred from direct assay Ref.2PubMed 15014045. Source: MGI neuronal cell body Inferred from direct assay Ref.2. Source: MGI pre-autophagosomal structure membrane Inferred from direct assay PubMed 18443221. Source: UniProtKB
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW protein serine/threonine kinase activity Inferred from direct assay PubMed 18443221. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 1051	1051	Serine/threonine-protein kinase ULK1		PRO_0000086781
Regions
	Domain	16 – 278	263	Protein kinase
	Nucleotide binding	22 – 30	9	ATP By similarity
	Compositional bias	297 – 310	14	Poly-Ser
Sites
	Active site	138	1	Proton acceptor By similarity
	Binding site	46	1	ATP Probable
Amino acid modifications
	Modified residue	317	1	Phosphoserine; by AMPK Ref.7
	Modified residue	450	1	Phosphoserine By similarity
	Modified residue	456	1	Phosphothreonine By similarity
	Modified residue	467	1	Phosphoserine Ref.8
	Modified residue	477	1	Phosphoserine By similarity
	Modified residue	479	1	Phosphoserine By similarity
	Modified residue	555	1	Phosphoserine; by AMPK Ref.8
	Modified residue	574	1	Phosphothreonine Ref.8
	Modified residue	624	1	Phosphothreonine Ref.4
	Modified residue	637	1	Phosphoserine; by AMPK Ref.4 Ref.8
	Modified residue	757	1	Phosphoserine; by MTOR Ref.7
	Modified residue	777	1	Phosphoserine; by AMPK Ref.7
Experimental info
	Mutagenesis	46	1	K → R: Loss of kinase activity and autophosphorylation. Ref.7 Ref.8
	Mutagenesis	317	1	S → A: Impairs phosphorylation by AMPK and ability to promote autophagy; when associated with A-777. Ref.7
	Mutagenesis	494	1	S → A: Does not affect phosphorylation by AMPK in vitro. Ref.7
	Mutagenesis	555	1	S → A: Does not affect phosphorylation by AMPK in vitro. Ref.7
	Mutagenesis	574	1	T → A: Does not affect phosphorylation by AMPK in vitro. Ref.7
	Mutagenesis	622	1	S → A: Does not affect phosphorylation by AMPK in vitro. Ref.7
	Mutagenesis	624	1	T → A: Does not affect phosphorylation by AMPK in vitro. Ref.7
	Mutagenesis	693	1	S → A: Does not affect phosphorylation by AMPK in vitro. Ref.7
	Mutagenesis	757	1	S → A or D: Impairs interaction with AMPK and subsequent phosphorylation by AMPK. Ref.7
	Mutagenesis	777	1	S → A: Impairs phosphorylation by AMPK and ability to promote autophagy; when associated with A-317. Ref.7
	Mutagenesis	811	1	S → A: Does not affect phosphorylation by AMPK in vitro. Ref.7
	Sequence conflict	469	1	T → S in AAH57121. Ref.3

Sequences

	Sequence		Length	Mass (Da)
	O70405 [UniParc]. Last modified August 1, 1998. Version 1. Checksum: 99B021985FB4E8A0	FASTA	1,051	112,463
	10 20 30 40 50 60 MEPGRGGVET VGKFEFSRKD LIGHGAFAVV FKGRHREKHD LEVAVKCINK KNLAKSQTLL 70 80 90 100 110 120 GKEIKILKEL KHENIVALYD FQEMANSVYL VMEYCNGGDL ADYLHTMRTL SEDTVRLFLQ 130 140 150 160 170 180 QIAGAMRLLH SKGIIHRDLK PQNILLSNPG GRRANPSNIR VKIADFGFAR YLQSNMMAAT 190 200 210 220 230 240 LCGSPMYMAP EVIMSQHYDG KADLWSIGTI VYQCLTGKAP FQASSPQDLR LFYEKNKTLV 250 260 270 280 290 300 PAIPRETSAP LRQLLLALLQ RNHKDRMDFD EFFHHPFLDA STPIKKSPPV PVPSYPSSGS 310 320 330 340 350 360 GSSSSSSSAS HLASPPSLGE MPQLQKTLTS PADAAGFLQG SRDSGGSSKD SCDTDDFVMV 370 380 390 400 410 420 PAQFPGDLVA EAASAKPPPD SLLCSGSSLV ASAGLESHGR TPSPSPTCSS SPSPSGRPGP 430 440 450 460 470 480 FSSNRYGASV PIPVPTQVHN YQRIEQNLQS PTQQQTARSS AIRRSGSTTP LGFGRASPSP 490 500 510 520 530 540 PSHTDGAMLA RKLSLGGGRP YTPSPQVGTI PERPSWSRVP SPQGADVRVG RSPRPGSSVP 550 560 570 580 590 600 EHSPRTTGLG CRLHSAPNLS DFHVVRPKLP KPPTDPLGAT FSPPQTSAPQ PCPGLQSCRP 610 620 630 640 650 660 LRGSPKLPDF LQRSPLPPIL GSPTKAGPSF DFPKTPSSQN LLTLLARQGV VMTPPRNRTL 670 680 690 700 710 720 PDLSEASPFH GQQLGSGLRP AEDTRGPFGR SFSTSRITDL LLKAAFGTQA SDSGSTDSLQ 730 740 750 760 770 780 EKPMEIAPSA GFGGTLHPGA RGGGASSPAP VVFTVGSPPS GATPPQSTRT RMFSVGSSSS 790 800 810 820 830 840 LGSTGSSSAR HLVPGACGEA PELSAPGHCC SLADPLAANL EGAVTFEAPD LPEETLMEQE 850 860 870 880 890 900 HTETLHSLRF TLAFAQQVLE IAALKGSASE AAGGPEYQLQ ESVVADQISQ LSREWGFAEQ 910 920 930 940 950 960 LVLYLKVAEL LSSGLQTAID QIRAGKLCLS STVKQVVRRL NELYKASVVS CQGLSLRLQR 970 980 990 1000 1010 1020 FFLDKQRLLD GIHGVTAERL ILSHAVQMVQ SAALDEMFQH REGCVPRYHK ALLLLEGLQH 1030 1040 1050 TLTDQADIEN IAKCKLCIER RLSALLSGVY A

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Identification of mouse ULK1, a novel protein kinase structurally related to C. elegans UNC-51." Yan J., Kuroyanagi H., Kuroiwa A., Matsuda Y., Tokumitsu H., Tomoda T., Shirasawa T., Muramatsu M.-A. Biochem. Biophys. Res. Commun. 246:222-227(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Brain.
[2]	"A mouse serine/threonine kinase homologous to C. elegans UNC51 functions in parallel fiber formation of cerebellar granule neurons." Tomoda T., Bhatt R.S., Kuroyanagi H., Shirasawa T., Hatten M.E. Neuron 24:833-846(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION. Strain: C57BL/6J. Tissue: Brain.
[3]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: C57BL/6. Tissue: Brain.
[4]	"Large-scale phosphorylation analysis of mouse liver." Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-624 AND SER-637, MASS SPECTROMETRY. Tissue: Liver.
[5]	"ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy." Ganley I.G., Lam du H., Wang J., Ding X., Chen S., Jiang X. J. Biol. Chem. 284:12297-12305(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH ATG13 AND RB1CC1, PHOSPHORYLATION, SUBCELLULAR LOCATION.
[6]	"Ulk1-mediated phosphorylation of AMPK constitutes a negative regulatory feedback loop." Loffler A.S., Alers S., Dieterle A.M., Keppeler H., Franz-Wachtel M., Kundu M., Campbell D.G., Wesselborg S., Alessi D.R., Stork B. Autophagy 7:696-706(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF AMPK.
[7]	"AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1." Kim J., Kundu M., Viollet B., Guan K.L. Nat. Cell Biol. 13:132-141(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, AUTOPHOSPHORYLATION, PHOSPHORYLATION AT SER-317; SER-757 AND SER-777, MUTAGENESIS OF LYS-46; SER-317; SER-494; SER-555; THR-574; SER-622; THR-624; SER-693; SER-757; SER-777 AND SER-811.
[8]	"Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy." Egan D.F., Shackelford D.B., Mihaylova M.M., Gelino S., Kohnz R.A., Mair W., Vasquez D.S., Joshi A., Gwinn D.M., Taylor R., Asara J.M., Fitzpatrick J., Dillin A., Viollet B., Kundu M., Hansen M., Shaw R.J. Science 331:456-461(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, AUTOPHOSPHORYLATION, PHOSPHORYLATION AT SER-467; SER-555; THR-574 AND SER-637, MUTAGENESIS OF LYS-46.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF053756 mRNA. Translation: AAC40118.1. AF072370 mRNA. Translation: AAF23317.1. BC057121 mRNA. Translation: AAH57121.1.
IPI	IPI00752067.
PIR	JW0051.
RefSeq	NP_033495.2. NM_009469.3.
UniGene	Mm.271898.
3D structure databases
ProteinModelPortal	O70405.
SMR	O70405. Positions 11-295.
ModBase	Search...
PTM databases
PhosphoSite	O70405.
Proteomic databases
PaxDb	O70405.
PRIDE	O70405.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000031490; ENSMUSP00000031490; ENSMUSG00000029512.
GeneID	22241.
KEGG	mmu:22241.
UCSC	uc008yrq.1. mouse.
Organism-specific databases
CTD	8408.
MGI	MGI:1270126. Ulk1.
Phylogenomic databases
eggNOG	COG0515.
GeneTree	ENSGT00700000104114.
HOGENOM	HOG000044146.
HOVERGEN	HBG000342.
KO	K08269.
OrthoDB	EOG4NS39T.
Enzyme and pathway databases
BRENDA	2.7.11.1. 3474.
Gene expression databases
ArrayExpress	O70405.
Bgee	O70405.
CleanEx	MM_ULK1.
Genevestigator	O70405.
GermOnline	ENSMUSG00000029512. Mus musculus.
Family and domain databases
InterPro	IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR002290. Ser/Thr_dual-sp_kinase_dom. IPR016237. Ser/Thr_kin_STPK_Ulk-1/2. IPR008271. Ser/Thr_kinase_AS. IPR022708. Ser/Thr_kinase_C. [Graphical view]
Pfam	PF12063. DUF3543. 1 hit. PF00069. Pkinase. 1 hit. [Graphical view]
PIRSF	PIRSF000580. Ser/Thr_PK_STPK_ULK-1/2. 1 hit.
SMART	SM00220. S_TKc. 1 hit. [Graphical view]
SUPFAM	SSF56112. Kinase_like. 1 hit.
PROSITE	PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	302305.
SOURCE	Search...

Entry information

Entry name

ULK1_MOUSE

Accession

Primary (citable) accession number: O70405
Secondary accession number(s): Q6PGB2

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1999
Last sequence update:	August 1, 1998
Last modified:	May 29, 2013
This is version 114 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program