| IED ID | IndEnz0002003148 |
| Enzyme Type ID | protease003148 |
| Protein Name |
Forkhead box protein O FOXO Abnormal dauer formation protein 16 |
| Gene Name | daf-16 R13H8.1 |
| Organism | Caenorhabditis elegans |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Protostomia Ecdysozoa Nematoda (roundworms) Chromadorea Rhabditida Rhabditina Rhabditomorpha Rhabditoidea Rhabditidae Peloderinae Caenorhabditis Caenorhabditis elegans |
| Enzyme Sequence | MQLEQKSSLHCSKCRNFLQKFSQDMQAWNCRELDSPLPSDITLHNLEPARPDSGMSFSTDFDDDFFNLDLHQQERSASFGGVTQYSQQFLREKCSFSPYFHTSLETVDSGRTSLYGSNEQCGQLGGASSNGSTAMLHTPDGSNSHQTSFPSDFRMSESPDDTVSGKKTTTRRNAWGNMSYAELITTAIMASPEKRLTLAQVYEWMVQNVPYFRDKGDSNSSAGWKNSIRHNLSLHSRFMRIQNEGAGKSSWWVINPDAKPGRNPRRTRERSNTIETTTKAQLEKSRRGAKKRIKERALMGSLHSTLNGNSIAGSIQTISHDLYDDDSMQGAFDNVPSSFRPRTQSNLSIPGSSSRVSPAIGSDIYDDLEFPSWVGESVPAIPSDIVDRTDQMRIDATTHIGGVQIKQESKPIKTEPIAPPPSYHELNSVRGSCAQNPLLRNPIVPSTNFKPMPLPGAYGNYQNGGITPINWLSTSNSSPLPGIQSCGIVAAQHTVASSSALPIDLENLTLPDQPLMDTMDVDALIRHELSQAGGQHIHFDL |
| Enzyme Length | 541 |
| Uniprot Accession Number | O16850 |
| Absorption | |
| Active Site | |
| Activity Regulation | |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | |
| DNA Binding | DNA_BIND 175..268; /note=Fork-head; /evidence=ECO:0000255|PROSITE-ProRule:PRU00089 |
| EC Number | |
| Enzyme Function | FUNCTION: Forkhead-type transcription factor (PubMed:9360933). Binds to the promoters of genes that contain the daf-16/FOXO binding element (DBE), TTGTTTAC, in their regulatory region (PubMed:10880363, PubMed:23770237, PubMed:26675724). Functions in the Insulin/IGF-1-like signaling (IIS) mediated pathway which affects lipogenesis, lifespan, starvation survival, heat shock and oxidative stress responses, sleep, associative memory, and dauer formation (PubMed:9360933, PubMed:8247153, PubMed:11747821, PubMed:11747825, PubMed:11381260, PubMed:14622602, PubMed:12750521, PubMed:17900900, PubMed:18358814, PubMed:18762027, PubMed:18832074, PubMed:19103192, PubMed:21531333, PubMed:22081913, PubMed:29523076, PubMed:26675724). Longevity signaling predominantly arises from expression in the intestine (PubMed:14622602). Transcriptional activity of daf-16/FOXO is negatively regulated by interaction with host cell factor homolog hcf-1; and by cytoplasmic sequestration by association with ftt-2 (PubMed:11381260, PubMed:21531333, PubMed:18828672). Inhibition is required for the carbon dioxide (CO2) avoidance response (PubMed:18524954). Upon loss of inhibition, daf-16 translocates to the nucleus to regulate genes that result in delayed reproduction and growth while increasing stress resistance starvation tolerance and longevity (PubMed:11747825, PubMed:21531333). Association with arginine methyltransferase prmt-1 prevents phosphorylation and allows for translocation to the nucleus and the subsequent transcription of longevity-related genes (PubMed:21531333). Modulation of its activity by cGMP levels in sensory neurons regulates lifespan (PubMed:19489741). Has a protective role against muscle dystrophy (PubMed:18397876). Involved in mediating protection against aberrant protein aggregation proteotoxicity (PubMed:16902091). Influences transcription of genes that code for proteins involved in immunity as part of a general stress response (PubMed:17096597, PubMed:18245330). Targets genes that inhibit and stimulate tumor growth (PubMed:17934462). Targets kinases, phosphatases and transcription factors that are primarily involved in signaling and gene regulation (PubMed:24516399). Thought to regulate ins-7 in FOXO-to-FOXO signaling, which coordinates daf-16 expression (PubMed:18025456). Activity is positively regulated by shc-1-mediated inhibition of daf-2 and activation of JNK pathway (PubMed:18832074). Functions by indirect interaction with jnk-1 of the mitogen-activated protein kinase (MAPK) pathway (PubMed:17894411). Involved in increased proteasome activity by activating expression of rpn-6.1 in response to proteotoxic stress, leading to enhanced assembly of the 26S proteasome, followed by higher proteasome activity (PubMed:22922647). Also regulates proteasome activity in the intestine by preventing expression of deubiquitinase ubh-4 (PubMed:23770237). Represses transcription of natc-1 (PubMed:25330323). Involved in regulation of srh-234 expression (PubMed:25357003). Binds to the promoter of the AMPK-gamma regulatory subunit, aakg-4, and activates its transcription (PubMed:24516399). Also activates transcription of AMPK-gamma regulatory subunit, aakg-1 (PubMed:24516399). Maintains endoplasmic reticulum (ER) function by inducing protein degradation and elimination to remove misfolded secretory proteins from the ER independently of the ire-1/xbp-1 unfolded protein response pathway (PubMed:25448701). Regulates epidermal innate immunity to nematophagous fungal infection and physical wounding which trigger bli-3 induced ROS release, leading to daf-16 activation independently of daf-2 signaling (PubMed:24146615). May negatively regulate resistance to stress caused by oxidized cholesterol adducts by preventing the activation of daf-9 and nuclear hormone receptor daf-12, two members of the steroid signaling pathway (PubMed:24957743). Promotes apoptosis during embryonic development (PubMed:25383666). Probably through the regulation of the autophagy genes atg-18 and atg-16.2, plays a role in regulating stem cell number in the germline during larval development (PubMed:28285998). Plays a role in learning and memory; including associative memory, and aversive gustatory associated learning known as salt avoidance learning (PubMed:26675724, PubMed:30779740). Plays a role in regulating gene transcription in response to white light exposure (PubMed:29500338). Binds to the promoter of dex-1 to positively regulate its expression in seam cells during the dauer phase (PubMed:30409788). {ECO:0000269|PubMed:10880363, ECO:0000269|PubMed:11381260, ECO:0000269|PubMed:11747821, ECO:0000269|PubMed:11747825, ECO:0000269|PubMed:12750521, ECO:0000269|PubMed:14622602, ECO:0000269|PubMed:16902091, ECO:0000269|PubMed:17096597, ECO:0000269|PubMed:17894411, ECO:0000269|PubMed:17900900, ECO:0000269|PubMed:17934462, ECO:0000269|PubMed:18025456, ECO:0000269|PubMed:18245330, ECO:0000269|PubMed:18358814, ECO:0000269|PubMed:18397876, ECO:0000269|PubMed:18524954, ECO:0000269|PubMed:18762027, ECO:0000269|PubMed:18832074, ECO:0000269|PubMed:19103192, ECO:0000269|PubMed:19489741, ECO:0000269|PubMed:21531333, ECO:0000269|PubMed:22081913, ECO:0000269|PubMed:22922647, ECO:0000269|PubMed:23770237, ECO:0000269|PubMed:24146615, ECO:0000269|PubMed:24516399, ECO:0000269|PubMed:24957743, ECO:0000269|PubMed:25330323, ECO:0000269|PubMed:25357003, ECO:0000269|PubMed:25383666, ECO:0000269|PubMed:25448701, ECO:0000269|PubMed:28285998, ECO:0000269|PubMed:29500338, ECO:0000269|PubMed:30409788, ECO:0000269|PubMed:30779740, ECO:0000269|PubMed:8247153, ECO:0000269|PubMed:9360933}.; FUNCTION: [Isoform a]: Functions in the Insulin/IGF-1-like signaling (IIS) mediated pathway (PubMed:24834345). May play a role in lifespan modulation, but less significant than that played by isoforms d and f (PubMed:24834345). {ECO:0000269|PubMed:24834345}.; FUNCTION: [Isoform d]: Functions in the Insulin/IGF-1-like signaling (IIS) mediated pathway (PubMed:24834345). Transcript level in the early adult may play a role in lifespan modulation, but effect is more significant than that played by isoform a (PubMed:24834345). {ECO:0000269|PubMed:24834345}.; FUNCTION: [Isoform f]: Functions in the Insulin/IGF-1-like signaling (IIS) mediated pathway (PubMed:24834345). Transcript level in the early adult may play a role in lifespan modulation, but effect is more significant than that played by isoform a (PubMed:24834345). {ECO:0000269|PubMed:24834345}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Alternative sequence (8); Chain (1); Compositional bias (1); DNA binding (1); Modified residue (2); Mutagenesis (10); Region (2) |
| Keywords | Alternative splicing;Cytoplasm;DNA-binding;Developmental protein;Growth regulation;Immunity;Innate immunity;Nucleus;Phosphoprotein;Reference proteome;Repressor;Stress response;Transcription;Transcription regulation;Ubl conjugation |
| Interact With | Q17941; Q9XTG7; Q2PJ68; Q21921 |
| Induction | INDUCTION: Induced by quinic acid. {ECO:0000269|PubMed:22950425}. |
| Subcellular Location | SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:11381260, ECO:0000269|PubMed:11747825, ECO:0000269|PubMed:15767565, ECO:0000269|PubMed:15888317, ECO:0000269|PubMed:17551714, ECO:0000269|PubMed:17894411, ECO:0000269|PubMed:18832074, ECO:0000269|PubMed:19252938, ECO:0000269|PubMed:21531333, ECO:0000269|PubMed:23805378, ECO:0000269|PubMed:24146615}. Cytoplasm {ECO:0000269|PubMed:11381260, ECO:0000269|PubMed:11747825, ECO:0000269|PubMed:15767565, ECO:0000269|PubMed:15888317, ECO:0000269|PubMed:17551714, ECO:0000269|PubMed:17894411, ECO:0000269|PubMed:18832074, ECO:0000269|PubMed:19252938, ECO:0000269|PubMed:21531333, ECO:0000269|PubMed:23805378, ECO:0000269|PubMed:24146615}. Note=Shuttles between cytoplasm and nucleus (PubMed:11381260, PubMed:17894411). Nuclear translocation is inhibited by phosphorylation by AKT proteins (PubMed:11381260, PubMed:11747825, PubMed:21531333). Association with ftt-2 sequesters daf-16 in the cytoplasm (PubMed:21531333). Association with prmt-1 allows for translocation to the nucleus (PubMed:21531333). Nuclear translocation is promoted by phosphorylation by unc-43 and inhibited by dephosphorylation by tax-6 (PubMed:23805378). Nuclear translocation is promoted by jnk-1 upon heat stress and by sek-1 upon oxidative stress (PubMed:15888317, PubMed:15767565). Nucleocytoplasmic shuttling is induced by starvation, heat treatment, hypergravity, reactive oxygen species (generated by juglone), exposure to tributyltin or 4-hydroxy-E-globularinin (4-HEG) and the flavonoids kaempferol and fisetin (PubMed:11381260, PubMed:17551714, PubMed:18832074, PubMed:19252938, PubMed:21531333, PubMed:23805378). Nuclear localization induced by nematophagous fungal infection (PubMed:24146615). {ECO:0000269|PubMed:11381260, ECO:0000269|PubMed:11747825, ECO:0000269|PubMed:15767565, ECO:0000269|PubMed:15888317, ECO:0000269|PubMed:17551714, ECO:0000269|PubMed:17894411, ECO:0000269|PubMed:18832074, ECO:0000269|PubMed:19252938, ECO:0000269|PubMed:21531333, ECO:0000269|PubMed:24146615}.; SUBCELLULAR LOCATION: [Isoform a]: Nucleus {ECO:0000269|PubMed:24834345}. Cytoplasm {ECO:0000269|PubMed:24834345}. Note=Ratio of nuclear to cytoplasmic localization is daf-2-dependent. {ECO:0000269|PubMed:24834345}.; SUBCELLULAR LOCATION: [Isoform d]: Nucleus {ECO:0000269|PubMed:24834345}. Cytoplasm {ECO:0000269|PubMed:24834345}. Note=Ratio of nuclear to cytoplasmic localization is daf-2-dependent. {ECO:0000269|PubMed:24834345}.; SUBCELLULAR LOCATION: [Isoform f]: Nucleus {ECO:0000269|PubMed:24834345}. Cytoplasm {ECO:0000269|PubMed:24834345}. Note=Ratio of nuclear to cytoplasmic localization is daf-2-dependent. {ECO:0000269|PubMed:24834345}. |
| Modified Residue | MOD_RES 273; /note=Phosphothreonine; /evidence=ECO:0000269|PubMed:21531333; MOD_RES 319; /note=Phosphoserine; by CaMK2; /evidence=ECO:0000269|PubMed:23805378 |
| Post Translational Modification | PTM: Phosphorylated by akt-1 and/or akt-2 (PubMed:18358814, PubMed:21531333). Phosphorylated by sgk-1 (PubMed:18358814). Phosphorylated by unc-43 (PubMed:23805378). Phosphorylated by jnk-1 (PubMed:15767565). Dephosphorylated by tax-6 in vitro (PubMed:23805378). {ECO:0000269|PubMed:15767565, ECO:0000269|PubMed:18358814, ECO:0000269|PubMed:21531333, ECO:0000269|PubMed:23805378}.; PTM: Ubiquitinated. Ubiquitination by rle-1 leads to proteasome-mediated degradation. {ECO:0000269|PubMed:17276341}.; PTM: Methylation by prmt-1 prevents phosphorylation and promotes translocation to the nucleus to allow for daf-16-dependent transcription. {ECO:0000269|PubMed:21531333}. |
| Signal Peptide | |
| Structure 3D | |
| Cross Reference PDB | - |
| Mapped Pubmed ID | 10778742; 10973497; 10978280; 11124266; 11259381; 11782415; 12097347; 12470895; 12571101; 12690206; 12817143; 12844535; 12845331; 12882324; 12966085; 14516929; 14704431; 15068796; 15253933; 15308663; 15314028; 15383841; 15653505; 15829632; 15905404; 16040138; 16151516; 16153634; 16280150; 16380712; 16442538; 16457721; 16458514; 16530049; 16530050; 16751106; 16777607; 16860373; 16916933; 17020605; 17081157; 17098225; 17164286; 17183709; 17244357; 17266680; 17276923; 17277769; 1732156; 17483415; 17513831; 17526726; 17720915; 17825044; 18006689; 18033297; 18050504; 18077331; 18182484; 18241854; 18285659; 18409080; 18467495; 18522834; 18538371; 18599512; 18676815; 18692520; 18728216; 18782349; 18854822; 18927620; 18988854; 19050081; 19123269; 19240135; 19249087; 19273594; 19343510; 19370397; 19372390; 19428455; 19454349; 19506556; 19597959; 19667176; 19706382; 19747231; 19747232; 19858203; 19883616; 19924292; 19952414; 20090912; 20140911; 20209166; 20368426; 20439774; 20439776; 20460307; 20477758; 20523893; 20549717; 20613724; 20620993; 20624915; 20668681; 20706209; 20816092; 20828537; 20944013; 21040400; 21057967; 21078113; 21085631; 21124868; 21129974; 21177967; 21203999; 21209831; 21288028; 21288877; 21367940; 21408062; 21463460; 21474712; 21477590; 21533078; 21546381; 21571636; 21593014; 21618079; 21695191; 21723504; 21839827; 21892924; 21906946; 21907144; 21931751; 21938618; 21945834; 22069193; 22155175; 22212395; 22212533; 22265419; 22267497; 22286215; 22347378; 22359667; 22396654; 22445852; 22482727; 22509016; 22554143; 22560223; 22560298; 22792076; 22875856; 22916022; 22935616; 22956852; 23028355; 23097426; 23247094; 23255046; 23300463; 23312285; 23333309; 23341633; 23352664; 23410029; 23419779; 23477722; 23516373; 23533643; 23549480; 23566034; 23586691; 23604319; 23624124; 23664972; 23665919; 23727258; 23733789; 23791175; 23791784; 23800452; 23818874; 23820781; 23894595; 23911329; 23959012; 24120884; 24123695; 2428682; 24406377; 24440228; 24472780; 24531613; 24552710; 24555535; 24671950; 24882066; 24884423; 24945567; 24945623; 24972867; 25419847; 25469508; 25487147; 25497095; 25510338; 25517099; 25762526; 25960195; 26154057; 26195740; 26219299; 26363351; 26539642; 26592451; 26656736; 26862916; 26919641; 26963674; 27001890; 27027346; 27090484; 27275864; 27370100; 27550812; 27557896; 27564576; 27573184; 27690135; 27730721; 27783623; 27838822; 27854075; 27905558; 27906968; 27989925; 28105749; 28119052; 28128482; 28196094; 28209513; 28549065; 28612944; 28638078; 28696216; 28766017; 29433733; 29514099; 29874838; 29924347; 30031267; 30120932; 30178731; 30250464; 30263604; 30291110; 30353013; 30478249; 30638295; 30710163; 30731110; 30773782; 30889411; 31017874; 31152844; 31246952; 31323047; 31906434; 31954516; 32161088; 32578648; 32636256; 32722431; 32733632; 32829877; 32841230; 32901024; 32997655; 33171300; 33891586; 33940230; 34014977; 34109380; 34203560; 34488090; 34780472; 34798183; 34830338; 6583682; 6593563; 7219552; 7789761; |
| Motif | |
| Gene Encoded By | |
| Mass | 59,732 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | |
| Cross Reference Brenda |