| IED ID | IndEnz0002011977 |
| Enzyme Type ID | protease011977 |
| Protein Name |
Serine/threonine-protein kinase ULK1 EC 2.7.11.1 Autophagy-related protein 1 homolog ATG1 hATG1 Unc-51-like kinase 1 |
| Gene Name | ULK1 KIAA0722 |
| Organism | Homo sapiens (Human) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Primates Haplorrhini Simiiformes Catarrhini Hominoidea (apes) Hominidae (great apes) Homininae Homo Homo sapiens (Human) |
| Enzyme Sequence | MEPGRGGTETVGKFEFSRKDLIGHGAFAVVFKGRHREKHDLEVAVKCINKKNLAKSQTLLGKEIKILKELKHENIVALYDFQEMANSVYLVMEYCNGGDLADYLHAMRTLSEDTIRLFLQQIAGAMRLLHSKGIIHRDLKPQNILLSNPAGRRANPNSIRVKIADFGFARYLQSNMMAATLCGSPMYMAPEVIMSQHYDGKADLWSIGTIVYQCLTGKAPFQASSPQDLRLFYEKNKTLVPTIPRETSAPLRQLLLALLQRNHKDRMDFDEFFHHPFLDASPSVRKSPPVPVPSYPSSGSGSSSSSSSTSHLASPPSLGEMQQLQKTLASPADTAGFLHSSRDSGGSKDSSCDTDDFVMVPAQFPGDLVAEAPSAKPPPDSLMCSGSSLVASAGLESHGRTPSPSPPCSSSPSPSGRAGPFSSSRCGASVPIPVPTQVQNYQRIERNLQSPTQFQTPRSSAIRRSGSTSPLGFARASPSPPAHAEHGGVLARKMSLGGGRPYTPSPQVGTIPERPGWSGTPSPQGAEMRGGRSPRPGSSAPEHSPRTSGLGCRLHSAPNLSDLHVVRPKLPKPPTDPLGAVFSPPQASPPQPSHGLQSCRNLRGSPKLPDFLQRNPLPPILGSPTKAVPSFDFPKTPSSQNLLALLARQGVVMTPPRNRTLPDLSEVGPFHGQPLGPGLRPGEDPKGPFGRSFSTSRLTDLLLKAAFGTQAPDPGSTESLQEKPMEIAPSAGFGGSLHPGARAGGTSSPSPVVFTVGSPPSGSTPPQGPRTRMFSAGPTGSASSSARHLVPGPCSEAPAPELPAPGHGCSFADPITANLEGAVTFEAPDLPEETLMEQEHTEILRGLRFTLLFVQHVLEIAALKGSASEAAGGPEYQLQESVVADQISLLSREWGFAEQLVLYLKVAELLSSGLQSAIDQIRAGKLCLSSTVKQVVRRLNELYKASVVSCQGLSLRLQRFFLDKQRLLDRIHSITAERLIFSHAVQMVQSAALDEMFQHREGCVPRYHKALLLLEGLQHMLSDQADIENVTKCKLCIERRLSALLTGICA |
| Enzyme Length | 1050 |
| Uniprot Accession Number | O75385 |
| Absorption | |
| Active Site | ACT_SITE 138; /note="Proton acceptor"; /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, ECO:0000255|PROSITE-ProRule:PRU10027" |
| Activity Regulation | ACTIVITY REGULATION: Acetylation by KAT5/TIP60 stimulates the protein kinase activity (By similarity). The protein kinase activity is activated by unanchored 'Lys-63'-linked polyubiquitin chains: unanchored 'Lys-63'-linked polyubiquitin chains are catalyzed by TRIM32 in an AMBRA1-dependent manner (PubMed:31123703). {ECO:0000250|UniProtKB:O70405, ECO:0000269|PubMed:31123703}. |
| Binding Site | BINDING 46; /note="ATP"; /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, ECO:0000305|PubMed:20921139" |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000269|PubMed:18936157, ECO:0000269|PubMed:25126726, ECO:0000269|PubMed:28821708, ECO:0000269|PubMed:31123703};PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:17990; Evidence={ECO:0000269|PubMed:18936157, ECO:0000269|PubMed:25126726, ECO:0000269|PubMed:31123703}; CATALYTIC ACTIVITY: Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000269|PubMed:18936157};PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46609; Evidence={ECO:0000269|PubMed:18936157}; |
| DNA Binding | |
| EC Number | 2.7.11.1 |
| Enzyme Function | FUNCTION: Serine/threonine-protein kinase involved in autophagy in response to starvation (PubMed:18936157, PubMed:21460634, PubMed:21795849, PubMed:23524951, PubMed:25040165, PubMed:31123703). Acts upstream of phosphatidylinositol 3-kinase PIK3C3 to regulate the formation of autophagophores, the precursors of autophagosomes (PubMed:18936157, PubMed:21460634, PubMed:21795849, PubMed:25040165). 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 (PubMed:21795849). 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 (PubMed:21460634). May phosphorylate ATG13/KIAA0652 and RPTOR; however such data need additional evidences (PubMed:18936157). Plays a role early in neuronal differentiation and is required for granule cell axon formation (PubMed:11146101). May also phosphorylate SESN2 and SQSTM1 to regulate autophagy (PubMed:25040165). Phosphorylates FLCN, promoting autophagy (PubMed:25126726). Phosphorylates AMBRA1 in response to autophagy induction, releasing AMBRA1 from the cytoskeletal docking site to induce autophagosome nucleation (PubMed:20921139). Phosphorylates ATG4B, leading to inhibit autophagy by decreasing both proteolytic activation and delipidation activities of ATG4B (PubMed:28821708). {ECO:0000269|PubMed:11146101, ECO:0000269|PubMed:18936157, ECO:0000269|PubMed:20921139, ECO:0000269|PubMed:21460634, ECO:0000269|PubMed:21795849, ECO:0000269|PubMed:23524951, ECO:0000269|PubMed:25040165, ECO:0000269|PubMed:25126726, ECO:0000269|PubMed:28821708, ECO:0000269|PubMed:31123703}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | NP_BIND 22..30; /note=ATP; /evidence=ECO:0000255|PROSITE-ProRule:PRU00159 |
| Features | Active site (1); Beta strand (9); Binding site (1); Chain (1); Compositional bias (4); Domain (1); Erroneous initiation (1); Helix (13); Modified residue (18); Mutagenesis (1); Natural variant (8); Nucleotide binding (1); Region (5); Turn (2) |
| Keywords | 3D-structure;ATP-binding;Acetylation;Autophagy;Cytoplasm;Kinase;Nucleotide-binding;Phosphoprotein;Reference proteome;Serine/threonine-protein kinase;Transferase;Ubl conjugation |
| Interact With | Q9C0C7; Q9C0C7-3; O75143; Q96LT7-1; Q96LT7-2; Q9H0R8; P60520; P42858; Q9GZQ8; Q9BXW4; P42345; P04629; O15530; P54646; Q9Y478; Q8TDY2; Q8N122; Q9P2M4; Q9Y4K3; Itself |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000250}. Preautophagosomal structure {ECO:0000250}. 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. {ECO:0000250}. |
| Modified Residue | MOD_RES 162; /note="N6-acetyllysine"; /evidence="ECO:0000250|UniProtKB:O70405"; MOD_RES 317; /note="Phosphoserine; by AMPK"; /evidence="ECO:0000250|UniProtKB:O70405"; MOD_RES 403; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:23186163"; MOD_RES 450; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163"; MOD_RES 456; /note="Phosphothreonine"; /evidence="ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:20068231"; MOD_RES 467; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:23186163"; MOD_RES 469; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163"; MOD_RES 477; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:23186163"; MOD_RES 479; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:23186163"; MOD_RES 522; /note="Phosphoserine"; /evidence="ECO:0000250|UniProtKB:O70405"; MOD_RES 556; /note="Phosphoserine; by AMPK"; /evidence="ECO:0000269|PubMed:24767988, ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163"; MOD_RES 575; /note="Phosphothreonine"; /evidence="ECO:0000250|UniProtKB:O70405"; MOD_RES 607; /note="N6-acetyllysine"; /evidence="ECO:0000250|UniProtKB:O70405"; MOD_RES 636; /note="Phosphothreonine"; /evidence="ECO:0000250|UniProtKB:O70405"; MOD_RES 638; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163"; MOD_RES 639; /note="Phosphoserine"; /evidence="ECO:0000250|UniProtKB:O70405"; MOD_RES 758; /note="Phosphoserine; by MTOR"; /evidence="ECO:0000305|PubMed:21205641, ECO:0007744|PubMed:23186163"; MOD_RES 775; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:23186163" |
| Post Translational Modification | PTM: Autophosphorylated. Phosphorylated under nutrient-rich conditions; dephosphorylated during starvation or following treatment with rapamycin. Under nutrient sufficiency, phosphorylated by MTOR/mTOR, disrupting the interaction with AMPK and preventing activation of ULK1 (By similarity). In response to nutrient limitation, phosphorylated and activated by AMPK, leading to activate autophagy. {ECO:0000250, ECO:0000269|PubMed:21205641}.; PTM: Ubiquitinated via 'Lys-63'-linkage by a complex composed of AMBRA1 and TRAF6 following autophagy induction, promoting ULK1 stability and kinase activity. {ECO:0000269|PubMed:23524951}.; PTM: Acetylated by KAT5/TIP60 under autophagy induction, promoting protein kinase activity. {ECO:0000250|UniProtKB:O70405}. |
| Signal Peptide | |
| Structure 3D | X-ray crystallography (6) |
| Cross Reference PDB | 4WNO; 4WNP; 5CI7; 6HYO; 6MNH; 6QAS; |
| Mapped Pubmed ID | 15767674; 16616143; 16940348; 17353931; 17595159; 18439900; 19225151; 19258318; 19690328; 20562859; 20711500; 20937701; 21072212; 21258367; 21383122; 21460621; 21460630; 21475306; 21518141; 21560199; 21718402; 21819378; 22321011; 22498478; 22539723; 22585231; 22885598; 23027865; 23147242; 23291726; 23295650; 23372762; 23392225; 23478338; 23685627; 23716696; 23727157; 23849170; 23863160; 23878245; 23884233; 24013547; 24066173; 24119841; 24306881; 24603492; 24671035; 24705402; 24719330; 24955726; 25043686; 25266655; 25429619; 25541949; 25551253; 25678702; 25686248; 25701603; 25714809; 25723488; 25749095; 25761126; 25792739; 25892232; 25909887; 25925668; 25957282; 25980607; 26018823; 26103054; 26177209; 26183158; 26207339; 26275681; 26282792; 26299883; 26299944; 26310906; 26434594; 26687681; 26734992; 27023913; 27046250; 27068414; 27153534; 27387056; 27485354; 27510922; 27629431; 27679555; 27687210; 27731364; 27783190; 27864418; 27869123; 27871932; 27903966; 27932573; 27934868; 27935582; 28011640; 28032867; 28069524; 28073914; 28079894; 28146421; 28195531; 28401008; 28410240; 28430962; 28486929; 28498429; 28614291; 28639909; 28653878; 28677209; 28791376; 28806404; 28820317; 28821724; 28978086; 29091866; 29109831; 29128638; 29148569; 29156790; 29208687; 29233105; 29313410; 29321306; 29470986; 29487085; 29563162; 29929428; 30001707; 30021155; 30024813; 30042494; 30046135; 30055128; 30078736; 30093610; 30103670; 30154410; 30410117; 30459284; 30497781; 30517873; 30545560; 30596474; 30782972; 30808462; 30853401; 30891127; 30907226; 30957634; 31053714; 31160490; 31208283; 31267703; 31291454; 31311432; 31378785; 31524222; 31732843; 31733992; 31821132; 31913283; 31923418; 31951027; 31959741; 31985048; 31986961; 32035621; 32125086; 32168879; 32203415; 32317083; 32320653; 32393312; 32516310; 32516362; 32549974; 32693121; 32705220; 32773036; 32913252; 33037394; 33040463; 33149253; 33172148; 33201521; 33328309; 33463048; 33531625; 33572255; 33654220; 33669246; 33735626; 33898322; 33932238; 33988678; 34096600; 34107300; 34204950; 34224814; 34259310; 34421918; 34454184; |
| Motif | |
| Gene Encoded By | |
| Mass | 112,631 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | RHEA:17989; RHEA:17990; RHEA:46608; RHEA:46609 |
| Cross Reference Brenda | 2.7.11.1; |