ID NOTUM_DROME Reviewed; 671 AA. AC Q9VUX3; Q8T385; DT 29-APR-2015, integrated into UniProtKB/Swiss-Prot. DT 05-JUL-2004, sequence version 3. DT 05-OCT-2016, entry version 105. DE RecName: Full=Palmitoleoyl-protein carboxylesterase NOTUM {ECO:0000305}; DE EC=3.1.1.98 {ECO:0000250|UniProtKB:Q6P988}; DE AltName: Full=Protein Notum {ECO:0000303|PubMed:12015973}; DE AltName: Full=Protein wingful {ECO:0000303|PubMed:12000788}; DE AltName: Full=dNOTUM {ECO:0000303|PubMed:25731175}; DE Flags: Precursor; GN Name=Notum {ECO:0000303|PubMed:12015973, GN ECO:0000312|FlyBase:FBgn0044028}; GN Synonyms=wf {ECO:0000303|PubMed:12000788}; GN ORFNames=CG13076 {ECO:0000312|FlyBase:FBgn0044028}; OS Drosophila melanogaster (Fruit fly). OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Hexapoda; Insecta; OC Pterygota; Neoptera; Endopterygota; Diptera; Brachycera; Muscomorpha; OC Ephydroidea; Drosophilidae; Drosophila; Sophophora. OX NCBI_TaxID=7227; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], SUBCELLULAR LOCATION, AND INDUCTION. RX PubMed=12015973; DOI=10.1016/S1534-5807(02)00180-6; RA Giraldez A.J., Copley R.R., Cohen S.M.; RT "HSPG modification by the secreted enzyme Notum shapes the Wingless RT morphogen gradient."; RL Dev. Cell 2:667-676(2002). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], SUBCELLULAR LOCATION, AND INDUCTION. RX PubMed=12000788; DOI=10.1101/gad.991802; RA Gerlitz O., Basler K.; RT "Wingful, an extracellular feedback inhibitor of Wingless."; RL Genes Dev. 16:1055-1059(2002). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RC STRAIN=Berkeley; RX PubMed=10731132; DOI=10.1126/science.287.5461.2185; RA Adams M.D., Celniker S.E., Holt R.A., Evans C.A., Gocayne J.D., RA Amanatides P.G., Scherer S.E., Li P.W., Hoskins R.A., Galle R.F., RA George R.A., Lewis S.E., Richards S., Ashburner M., Henderson S.N., RA Sutton G.G., Wortman J.R., Yandell M.D., Zhang Q., Chen L.X., RA Brandon R.C., Rogers Y.-H.C., Blazej R.G., Champe M., Pfeiffer B.D., RA Wan K.H., Doyle C., Baxter E.G., Helt G., Nelson C.R., Miklos G.L.G., RA Abril J.F., Agbayani A., An H.-J., Andrews-Pfannkoch C., Baldwin D., RA Ballew R.M., Basu A., Baxendale J., Bayraktaroglu L., Beasley E.M., RA Beeson K.Y., Benos P.V., Berman B.P., Bhandari D., Bolshakov S., RA Borkova D., Botchan M.R., Bouck J., Brokstein P., Brottier P., RA Burtis K.C., Busam D.A., Butler H., Cadieu E., Center A., Chandra I., RA Cherry J.M., Cawley S., Dahlke C., Davenport L.B., Davies P., RA de Pablos B., Delcher A., Deng Z., Mays A.D., Dew I., Dietz S.M., RA Dodson K., Doup L.E., Downes M., Dugan-Rocha S., Dunkov B.C., Dunn P., RA Durbin K.J., Evangelista C.C., Ferraz C., Ferriera S., Fleischmann W., RA Fosler C., Gabrielian A.E., Garg N.S., Gelbart W.M., Glasser K., RA Glodek A., Gong F., Gorrell J.H., Gu Z., Guan P., Harris M., RA Harris N.L., Harvey D.A., Heiman T.J., Hernandez J.R., Houck J., RA Hostin D., Houston K.A., Howland T.J., Wei M.-H., Ibegwam C., RA Jalali M., Kalush F., Karpen G.H., Ke Z., Kennison J.A., Ketchum K.A., RA Kimmel B.E., Kodira C.D., Kraft C.L., Kravitz S., Kulp D., Lai Z., RA Lasko P., Lei Y., Levitsky A.A., Li J.H., Li Z., Liang Y., Lin X., RA Liu X., Mattei B., McIntosh T.C., McLeod M.P., McPherson D., RA Merkulov G., Milshina N.V., Mobarry C., Morris J., Moshrefi A., RA Mount S.M., Moy M., Murphy B., Murphy L., Muzny D.M., Nelson D.L., RA Nelson D.R., Nelson K.A., Nixon K., Nusskern D.R., Pacleb J.M., RA Palazzolo M., Pittman G.S., Pan S., Pollard J., Puri V., Reese M.G., RA Reinert K., Remington K., Saunders R.D.C., Scheeler F., Shen H., RA Shue B.C., Siden-Kiamos I., Simpson M., Skupski M.P., Smith T.J., RA Spier E., Spradling A.C., Stapleton M., Strong R., Sun E., RA Svirskas R., Tector C., Turner R., Venter E., Wang A.H., Wang X., RA Wang Z.-Y., Wassarman D.A., Weinstock G.M., Weissenbach J., RA Williams S.M., Woodage T., Worley K.C., Wu D., Yang S., Yao Q.A., RA Ye J., Yeh R.-F., Zaveri J.S., Zhan M., Zhang G., Zhao Q., Zheng L., RA Zheng X.H., Zhong F.N., Zhong W., Zhou X., Zhu S.C., Zhu X., RA Smith H.O., Gibbs R.A., Myers E.W., Rubin G.M., Venter J.C.; RT "The genome sequence of Drosophila melanogaster."; RL Science 287:2185-2195(2000). RN [4] RP GENOME REANNOTATION. RC STRAIN=Berkeley; RX PubMed=12537572; DOI=10.1186/gb-2002-3-12-research0083; RA Misra S., Crosby M.A., Mungall C.J., Matthews B.B., Campbell K.S., RA Hradecky P., Huang Y., Kaminker J.S., Millburn G.H., Prochnik S.E., RA Smith C.D., Tupy J.L., Whitfield E.J., Bayraktaroglu L., Berman B.P., RA Bettencourt B.R., Celniker S.E., de Grey A.D.N.J., Drysdale R.A., RA Harris N.L., Richter J., Russo S., Schroeder A.J., Shu S.Q., RA Stapleton M., Yamada C., Ashburner M., Gelbart W.M., Rubin G.M., RA Lewis S.E.; RT "Annotation of the Drosophila melanogaster euchromatic genome: a RT systematic review."; RL Genome Biol. 3:RESEARCH0083.1-RESEARCH0083.22(2002). RN [5] RP PRELIMINARY FUNCTION. RX PubMed=15469839; DOI=10.1016/j.devcel.2004.08.005; RA Kreuger J., Perez L., Giraldez A.J., Cohen S.M.; RT "Opposing activities of Dally-like glypican at high and low levels of RT Wingless morphogen activity."; RL Dev. Cell 7:503-512(2004). RN [6] RP FUNCTION. RX PubMed=20412775; DOI=10.1016/j.devcel.2010.02.015; RA Ayers K.L., Gallet A., Staccini-Lavenant L., Therond P.P.; RT "The long-range activity of Hedgehog is regulated in the apical RT extracellular space by the glypican Dally and the hydrolase Notum."; RL Dev. Cell 18:605-620(2010). RN [7] RP FUNCTION. RX PubMed=22872085; DOI=10.1242/dev.078402; RA Ayers K.L., Mteirek R., Cervantes A., Lavenant-Staccini L., RA Therond P.P., Gallet A.; RT "Dally and Notum regulate the switch between low and high level RT Hedgehog pathway signalling."; RL Development 139:3168-3179(2012). RN [8] RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 82-415 AND 598-617, FUNCTION, RP SUBCELLULAR LOCATION, GLYCOSYLATION AT ASN-95, AND MUTAGENESIS OF RP SER-237. RX PubMed=25731175; DOI=10.1038/nature14259; RA Kakugawa S., Langton P.F., Zebisch M., Howell S.A., Chang T.H., RA Liu Y., Feizi T., Bineva G., O'Reilly N., Snijders A.P., Jones E.Y., RA Vincent J.P.; RT "Notum deacylates Wnt proteins to suppress signalling activity."; RL Nature 519:187-192(2015). CC -!- FUNCTION: Carboxylesterase that acts as a key negative regulator CC of the Wnt signaling pathway by specifically mediating CC depalmitoleylation of WNT proteins. Serine palmitoleylation of WNT CC proteins is required for efficient binding to frizzled receptors CC (PubMed:25731175). Also acts as a regulator of long-range activity CC of Hedgehog (hh), possibly by regulating the switch between low CC and high level hh pathway signaling (PubMed:20412775, CC PubMed:22872085). {ECO:0000250|UniProtKB:Q6P988, CC ECO:0000269|PubMed:20412775, ECO:0000269|PubMed:22872085, CC ECO:0000269|PubMed:25731175}. CC -!- CATALYTIC ACTIVITY: [Wnt]-O-(9Z)-hexadec-9-enoyl-L-serine + H(2)O CC = [Wnt]-L-serine + (9Z)-hexadec-9-enoate. CC {ECO:0000250|UniProtKB:Q6P988}. CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:12000788, CC ECO:0000269|PubMed:12015973, ECO:0000269|PubMed:25731175}. Cell CC surface {ECO:0000269|PubMed:25731175}. Note=Associates with the CC cell surface via interaction with sulfated CAG chains on CC glypicans. {ECO:0000269|PubMed:25731175}. CC -!- INDUCTION: Expression is induced by Wnt. CC {ECO:0000269|PubMed:12000788, ECO:0000269|PubMed:12015973}. CC -!- SIMILARITY: Belongs to the pectinacetylesterase family. Notum CC subfamily. {ECO:0000305}. CC -!- CAUTION: The molecular function of NOTUM has remained unclear for CC many years. It was initially thought to hydrolyze CC glycosaminoglycan (GAG) chains of glypicans, thereby affecting CC glypicans ability to interact with Wnt ligands (PubMed:12015973, CC PubMed:12000788). It was later reported to trigger glypican CC shedding, by mediating cleavage of their GPI-anchor CC (PubMed:15469839). However, while NOTUM specifically inhibit the CC Wnt signaling pathway, more pleiotropic effects would be expected CC from an enzyme affecting glypicans. It was finally shown that it CC requires glypicans to suppress Wnt signaling, but does not cleave CC their GPI-anchor (PubMed:25731175). It acts by mediating CC depalmitoleylation of WNT proteins, impairing WNT binding to CC frizzled receptors (PubMed:25731175). CC {ECO:0000269|PubMed:25731175, ECO:0000305|PubMed:12000788, CC ECO:0000305|PubMed:12015973, ECO:0000305|PubMed:15469839}. CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=The art of biocuration CC - Issue 177 of March 2016; CC URL="http://web.expasy.org/spotlight/back_issues/177/"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AJ457833; CAD29885.1; -; mRNA. DR EMBL; AY078993; AAL85497.1; -; mRNA. DR EMBL; AE014296; AAF49550.3; -; Genomic_DNA. DR RefSeq; NP_730096.2; NM_168643.3. DR UniGene; Dm.12824; -. DR PDB; 4UZJ; X-ray; 2.40 A; A/B=86-415, A/B=598-617. DR PDB; 4UZK; X-ray; 1.90 A; A/B=82-415, A/B=598-617. DR PDBsum; 4UZJ; -. DR PDBsum; 4UZK; -. DR ProteinModelPortal; Q9VUX3; -. DR SMR; Q9VUX3; 86-415, 598-616, 619-668. DR DIP; DIP-61510N; -. DR IntAct; Q9VUX3; 2. DR STRING; 7227.FBpp0075193; -. DR ESTHER; drome-q9vux3; Pectinacetylesterase-Notum. DR PaxDb; Q9VUX3; -. DR PRIDE; Q9VUX3; -. DR EnsemblMetazoa; FBtr0075435; FBpp0075193; FBgn0044028. DR GeneID; 39751; -. DR KEGG; dme:Dmel_CG13076; -. DR UCSC; CG13076-RA; d. melanogaster. DR CTD; 147111; -. DR FlyBase; FBgn0044028; Notum. DR eggNOG; KOG4287; Eukaryota. DR eggNOG; ENOG410XQKD; LUCA. DR GeneTree; ENSGT00390000015892; -. DR OMA; SKRDWVN; -. DR OrthoDB; EOG091G04KM; -. DR Reactome; R-DME-5362798; Release of Hh-Np from the secreting cell. DR GenomeRNAi; 39751; -. DR PRO; PR:Q9VUX3; -. DR Proteomes; UP000000803; Chromosome 3L. DR Bgee; FBgn0044028; -. DR Genevisible; Q9VUX3; DM. DR GO; GO:0009986; C:cell surface; IEA:UniProtKB-SubCell. DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB. DR GO; GO:1990699; F:palmitoleyl hydrolase activity; ISS:UniProtKB. DR GO; GO:0006507; P:GPI anchor release; IMP:FlyBase. DR GO; GO:0030178; P:negative regulation of Wnt signaling pathway; IDA:UniProtKB. DR GO; GO:1990697; P:protein depalmitoleylation; ISS:UniProtKB. DR GO; GO:0006029; P:proteoglycan metabolic process; NAS:FlyBase. DR GO; GO:0048076; P:regulation of compound eye pigmentation; IMP:FlyBase. DR GO; GO:0007419; P:ventral cord development; IMP:FlyBase. DR GO; GO:0048190; P:wing disc dorsal/ventral pattern formation; IGI:FlyBase. DR GO; GO:0016055; P:Wnt signaling pathway; IMP:FlyBase. DR InterPro; IPR004963; PAE/NOTUM. DR PANTHER; PTHR21562; PTHR21562; 2. DR Pfam; PF03283; PAE; 1. PE 1: Evidence at protein level; KW 3D-structure; Complete proteome; Glycoprotein; Hydrolase; KW Reference proteome; Secreted; Serine esterase; Signal; KW Wnt signaling pathway. FT SIGNAL 1 46 {ECO:0000255}. FT CHAIN 47 671 Palmitoleoyl-protein carboxylesterase FT NOTUM. {ECO:0000255}. FT /FTId=PRO_0000432994. FT ACT_SITE 237 237 Charge relay system. FT {ECO:0000250|UniProtKB:Q6P988}. FT ACT_SITE 338 338 Charge relay system. FT {ECO:0000250|UniProtKB:Q6P988}. FT ACT_SITE 384 384 Charge relay system. FT {ECO:0000250|UniProtKB:Q6P988}. FT CARBOHYD 95 95 N-linked (GlcNAc...). FT {ECO:0000244|PDB:4UZJ, FT ECO:0000244|PDB:4UZK, FT ECO:0000269|PubMed:25731175}. FT CARBOHYD 372 372 N-linked (GlcNAc...). FT {ECO:0000255|PROSITE-ProRule:PRU00498}. FT CARBOHYD 578 578 N-linked (GlcNAc...). FT {ECO:0000255|PROSITE-ProRule:PRU00498}. FT CARBOHYD 612 612 N-linked (GlcNAc...). FT {ECO:0000255|PROSITE-ProRule:PRU00498}. FT MUTAGEN 237 237 S->A: Impaired ability to inhibit the Wnt FT signaling pathway. FT {ECO:0000269|PubMed:25731175}. FT STRAND 88 92 {ECO:0000244|PDB:4UZK}. FT STRAND 107 111 {ECO:0000244|PDB:4UZK}. FT STRAND 118 123 {ECO:0000244|PDB:4UZK}. FT HELIX 132 141 {ECO:0000244|PDB:4UZK}. FT HELIX 143 145 {ECO:0000244|PDB:4UZK}. FT STRAND 153 155 {ECO:0000244|PDB:4UZK}. FT HELIX 159 161 {ECO:0000244|PDB:4UZK}. FT TURN 165 167 {ECO:0000244|PDB:4UZK}. FT TURN 169 173 {ECO:0000244|PDB:4UZK}. FT STRAND 174 179 {ECO:0000244|PDB:4UZK}. FT STRAND 183 185 {ECO:0000244|PDB:4UZK}. FT STRAND 191 193 {ECO:0000244|PDB:4UZK}. FT HELIX 207 218 {ECO:0000244|PDB:4UZK}. FT HELIX 219 221 {ECO:0000244|PDB:4UZK}. FT TURN 222 224 {ECO:0000244|PDB:4UZK}. FT STRAND 229 236 {ECO:0000244|PDB:4UZK}. FT HELIX 238 255 {ECO:0000244|PDB:4UZK}. FT STRAND 262 270 {ECO:0000244|PDB:4UZK}. FT HELIX 286 297 {ECO:0000244|PDB:4UZK}. FT HELIX 303 308 {ECO:0000244|PDB:4UZK}. FT STRAND 309 311 {ECO:0000244|PDB:4UZJ}. FT HELIX 313 317 {ECO:0000244|PDB:4UZK}. FT HELIX 319 322 {ECO:0000244|PDB:4UZK}. FT HELIX 323 325 {ECO:0000244|PDB:4UZK}. FT STRAND 330 333 {ECO:0000244|PDB:4UZK}. FT HELIX 339 344 {ECO:0000244|PDB:4UZK}. FT HELIX 353 369 {ECO:0000244|PDB:4UZK}. FT TURN 370 372 {ECO:0000244|PDB:4UZK}. FT STRAND 374 378 {ECO:0000244|PDB:4UZK}. FT STRAND 380 384 {ECO:0000244|PDB:4UZK}. FT HELIX 390 393 {ECO:0000244|PDB:4UZK}. FT HELIX 402 412 {ECO:0000244|PDB:4UZK}. FT STRAND 601 603 {ECO:0000244|PDB:4UZK}. SQ SEQUENCE 671 AA; 76937 MW; 0230294B1E754D94 CRC64; MAVEQIDKMA AKAGEATNKW IKPQQPLLTL LLLLATFSQL PAVCSSSILD AASLQEKDPL RDTSMNMIQR NYMVMHSASG SGDHSRSLKR ANLANTSITC NDGSHAGFYL RKHPSSKKWI VLLEGGWHCF DVRSCRSRWM RLRHLMTSSQ WPETRDVGGI LSPHPEENPY WHNANHVLIP YCSSDSWSGT RTEPDTSDRE NSWRFMGALI LRQVIAELIP VGLGRVPGGE LMLVGSSAGG MGVMLNLDRI RDFLVNEKKL QITVRGVSDS GWFLDREPYT PAAVASNEAV RQGWKLWQGL LPEECTKSYP TEPWRCYYGY RLYPTLKTPL FVFQWLFDEA QMRVDNVGAP VTPQQWNYIH EMGGALRSSL DNVSAVFAPS CIGHGVLFKR DWVNIKIDDI SLPSALRCWE HSTRSRRHDK LKRSTEPSTA VSHPEHANNQ RHQRHRQRLQ RQKHNNVAQS GGQQRKHNHL SKEEREERKR LRQEQRQRRK QRRRQQQQKK ANGGQEHRNK KDNSPKSSNG NDQRKQRRRQ QLTAEERQEQ RKRRRKAQQQ QMKMQREQPA AGVFLEASAP QKTRSSNNAS AGTKSKKRHR VPRVPEKCGL RLLERCSWPQ CNHSCPTLTN PMTGEEMRFL ELLTAFGLDI EAVAAALGVD MHTLNNMERT ELVNMLTQQA N //