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 02-JUN-2021, entry version 132. 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, 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; Pterygota; OC Neoptera; Endopterygota; Diptera; Brachycera; Muscomorpha; Ephydroidea; OC 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., Brandon R.C., RA Rogers Y.-H.C., Blazej R.G., Champe M., Pfeiffer B.D., Wan K.H., Doyle C., RA Baxter E.G., Helt G., Nelson C.R., Miklos G.L.G., Abril J.F., Agbayani A., RA An H.-J., Andrews-Pfannkoch C., Baldwin D., Ballew R.M., Basu A., RA Baxendale J., Bayraktaroglu L., Beasley E.M., Beeson K.Y., Benos P.V., RA Berman B.P., Bhandari D., Bolshakov S., Borkova D., Botchan M.R., Bouck J., RA Brokstein P., Brottier P., Burtis K.C., Busam D.A., Butler H., Cadieu E., RA Center A., Chandra I., Cherry J.M., Cawley S., Dahlke C., Davenport L.B., RA Davies P., de Pablos B., Delcher A., Deng Z., Mays A.D., Dew I., RA Dietz S.M., Dodson K., Doup L.E., Downes M., Dugan-Rocha S., Dunkov B.C., RA Dunn P., Durbin K.J., Evangelista C.C., Ferraz C., Ferriera S., RA Fleischmann W., Fosler C., Gabrielian A.E., Garg N.S., Gelbart W.M., RA Glasser K., 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., Hostin D., RA Houston K.A., Howland T.J., Wei M.-H., Ibegwam C., Jalali M., Kalush F., RA Karpen G.H., Ke Z., Kennison J.A., Ketchum K.A., Kimmel B.E., Kodira C.D., RA Kraft C.L., Kravitz S., Kulp D., Lai Z., Lasko P., Lei Y., Levitsky A.A., RA Li J.H., Li Z., Liang Y., Lin X., Liu X., Mattei B., McIntosh T.C., RA McLeod M.P., McPherson D., Merkulov G., Milshina N.V., Mobarry C., RA Morris J., Moshrefi A., Mount S.M., Moy M., Murphy B., Murphy L., RA Muzny D.M., Nelson D.L., Nelson D.R., Nelson K.A., Nixon K., Nusskern D.R., RA Pacleb J.M., Palazzolo M., Pittman G.S., Pan S., Pollard J., Puri V., RA Reese M.G., Reinert K., Remington K., Saunders R.D.C., Scheeler F., RA Shen H., 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., Svirskas R., RA Tector C., Turner R., Venter E., Wang A.H., Wang X., Wang Z.-Y., RA Wassarman D.A., Weinstock G.M., Weissenbach J., Williams S.M., Woodage T., RA Worley K.C., Wu D., Yang S., Yao Q.A., Ye J., Yeh R.-F., Zaveri J.S., RA Zhan M., Zhang G., Zhao Q., Zheng L., Zheng X.H., Zhong F.N., Zhong W., RA Zhou X., Zhu S.C., Zhu X., Smith H.O., Gibbs R.A., Myers E.W., Rubin G.M., RA 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., Stapleton M., RA Yamada C., Ashburner M., Gelbart W.M., Rubin G.M., Lewis S.E.; RT "Annotation of the Drosophila melanogaster euchromatic genome: a systematic RT 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., Therond P.P., RA Gallet A.; RT "Dally and Notum regulate the switch between low and high level Hedgehog RT 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 SER-237. RX PubMed=25731175; DOI=10.1038/nature14259; RA Kakugawa S., Langton P.F., Zebisch M., Howell S.A., Chang T.H., Liu Y., RA Feizi T., Bineva G., O'Reilly N., Snijders A.P., Jones E.Y., 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 of the CC Wnt signaling pathway by specifically mediating depalmitoleoylation of CC WNT proteins. Serine palmitoleoylation of WNT proteins is required for CC efficient binding to frizzled receptors (PubMed:25731175). Also acts as CC a regulator of long-range activity of Hedgehog (hh), possibly by CC regulating the switch between low and high level hh pathway signaling CC (PubMed:20412775, PubMed:22872085). {ECO:0000250|UniProtKB:Q6P988, CC ECO:0000269|PubMed:20412775, ECO:0000269|PubMed:22872085, CC ECO:0000269|PubMed:25731175}. CC -!- CATALYTIC ACTIVITY: CC Reaction=[Wnt protein]-O-(9Z)-hexadecenoyl-L-serine + H2O = (9Z)- CC hexadecenoate + [Wnt protein]-L-serine + H(+); Xref=Rhea:RHEA:45340, CC Rhea:RHEA-COMP:11170, Rhea:RHEA-COMP:11171, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:32372, CC ChEBI:CHEBI:85189; EC=3.1.1.98; CC Evidence={ECO:0000250|UniProtKB:Q6P988}; CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:12000788, CC ECO:0000269|PubMed:12015973, ECO:0000269|PubMed:25731175}. Cell surface CC {ECO:0000269|PubMed:25731175}. Note=Associates with the cell surface CC via interaction with sulfated CAG chains on glypicans. CC {ECO:0000269|PubMed:25731175}. CC -!- INDUCTION: Expression is induced by Wnt. {ECO:0000269|PubMed:12000788, CC 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 many CC years. It was initially thought to hydrolyze glycosaminoglycan (GAG) CC chains of glypicans, thereby affecting glypicans ability to interact CC with Wnt ligands (PubMed:12015973, PubMed:12000788). It was later CC reported to trigger glypican shedding, by mediating cleavage of their CC GPI-anchor (PubMed:15469839). However, while NOTUM specifically inhibit CC the 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 their CC GPI-anchor (PubMed:25731175). It acts by mediating depalmitoleoylation CC of WNT proteins, impairing WNT binding to frizzled receptors CC (PubMed:25731175). {ECO:0000269|PubMed:25731175, CC ECO:0000305|PubMed:12000788, ECO:0000305|PubMed:12015973, CC ECO:0000305|PubMed:15469839}. CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=The art of biocuration CC - Issue 177 of March 2016; CC URL="https://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 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 SMR; Q9VUX3; -. DR DIP; DIP-61510N; -. DR IntAct; Q9VUX3; 2. DR STRING; 7227.FBpp0075193; -. DR ESTHER; drome-q9vux3; Pectinacetylesterase-Notum. DR iPTMnet; Q9VUX3; -. 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 GeneTree; ENSGT00940000173033; -. DR HOGENOM; CLU_026533_1_1_1; -. DR InParanoid; Q9VUX3; -. DR OMA; SKRDWVN; -. DR OrthoDB; 610784at2759; -. DR BRENDA; 3.1.1.98; 1994. DR Reactome; R-DME-381426; Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs). DR Reactome; R-DME-5362798; Release of Hh-Np from the secreting cell. DR Reactome; R-DME-8957275; Post-translational protein phosphorylation. DR BioGRID-ORCS; 39751; 0 hits in 1 CRISPR screen. DR GenomeRNAi; 39751; -. DR PRO; PR:Q9VUX3; -. DR Proteomes; UP000000803; Chromosome 3L. DR Bgee; FBgn0044028; Expressed in embryo and 16 other tissues. 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:0048546; P:digestive tract morphogenesis; IMP:FlyBase. DR GO; GO:0006507; P:GPI anchor release; IMP:FlyBase. DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IDA:UniProtKB. DR GO; GO:0045880; P:positive regulation of smoothened signaling pathway; IMP:FlyBase. DR GO; GO:1990697; P:protein depalmitoleylation; ISS:UniProtKB. DR GO; GO:0048076; P:regulation of compound eye pigmentation; IMP:FlyBase. DR GO; GO:0007419; P:ventral cord development; HMP:FlyBase. DR GO; GO:0035220; P:wing disc development; IMP:FlyBase. DR GO; GO:0048190; P:wing disc dorsal/ventral pattern formation; IGI:FlyBase. DR GO; GO:0035222; P:wing disc pattern formation; IMP:FlyBase. DR GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW. DR InterPro; IPR004963; PAE/NOTUM. DR PANTHER; PTHR21562; PTHR21562; 1. DR Pfam; PF03283; PAE; 1. PE 1: Evidence at protein level; KW 3D-structure; Glycoprotein; Hydrolase; Reference proteome; Secreted; KW Serine esterase; Signal; Wnt signaling pathway. FT SIGNAL 1..46 FT /evidence="ECO:0000255" FT CHAIN 47..671 FT /note="Palmitoleoyl-protein carboxylesterase NOTUM" FT /evidence="ECO:0000255" FT /id="PRO_0000432994" FT REGION 411..592 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 411..426 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 466..483 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 499..545 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 237 FT /note="Charge relay system" FT /evidence="ECO:0000250|UniProtKB:Q6P988" FT ACT_SITE 338 FT /note="Charge relay system" FT /evidence="ECO:0000250|UniProtKB:Q6P988" FT ACT_SITE 384 FT /note="Charge relay system" FT /evidence="ECO:0000250|UniProtKB:Q6P988" FT CARBOHYD 95 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:25731175, FT ECO:0007744|PDB:4UZJ, ECO:0007744|PDB:4UZK" FT CARBOHYD 372 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498" FT CARBOHYD 578 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498" FT CARBOHYD 612 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498" FT MUTAGEN 237 FT /note="S->A: Impaired ability to inhibit the Wnt signaling FT pathway." FT /evidence="ECO:0000269|PubMed:25731175" FT STRAND 88..92 FT /evidence="ECO:0007829|PDB:4UZK" FT STRAND 107..111 FT /evidence="ECO:0007829|PDB:4UZK" FT STRAND 118..123 FT /evidence="ECO:0007829|PDB:4UZK" FT HELIX 132..141 FT /evidence="ECO:0007829|PDB:4UZK" FT HELIX 143..145 FT /evidence="ECO:0007829|PDB:4UZK" FT STRAND 153..155 FT /evidence="ECO:0007829|PDB:4UZK" FT HELIX 159..161 FT /evidence="ECO:0007829|PDB:4UZK" FT TURN 165..167 FT /evidence="ECO:0007829|PDB:4UZK" FT TURN 169..173 FT /evidence="ECO:0007829|PDB:4UZK" FT STRAND 174..179 FT /evidence="ECO:0007829|PDB:4UZK" FT STRAND 183..185 FT /evidence="ECO:0007829|PDB:4UZK" FT STRAND 191..193 FT /evidence="ECO:0007829|PDB:4UZK" FT HELIX 207..218 FT /evidence="ECO:0007829|PDB:4UZK" FT HELIX 219..221 FT /evidence="ECO:0007829|PDB:4UZK" FT TURN 222..224 FT /evidence="ECO:0007829|PDB:4UZK" FT STRAND 229..236 FT /evidence="ECO:0007829|PDB:4UZK" FT HELIX 238..255 FT /evidence="ECO:0007829|PDB:4UZK" FT STRAND 262..270 FT /evidence="ECO:0007829|PDB:4UZK" FT HELIX 286..297 FT /evidence="ECO:0007829|PDB:4UZK" FT HELIX 303..308 FT /evidence="ECO:0007829|PDB:4UZK" FT STRAND 309..311 FT /evidence="ECO:0007829|PDB:4UZJ" FT HELIX 313..317 FT /evidence="ECO:0007829|PDB:4UZK" FT HELIX 319..322 FT /evidence="ECO:0007829|PDB:4UZK" FT HELIX 323..325 FT /evidence="ECO:0007829|PDB:4UZK" FT STRAND 330..333 FT /evidence="ECO:0007829|PDB:4UZK" FT HELIX 339..344 FT /evidence="ECO:0007829|PDB:4UZK" FT HELIX 353..369 FT /evidence="ECO:0007829|PDB:4UZK" FT TURN 370..372 FT /evidence="ECO:0007829|PDB:4UZK" FT STRAND 374..378 FT /evidence="ECO:0007829|PDB:4UZK" FT STRAND 380..384 FT /evidence="ECO:0007829|PDB:4UZK" FT HELIX 390..393 FT /evidence="ECO:0007829|PDB:4UZK" FT HELIX 402..412 FT /evidence="ECO:0007829|PDB:4UZK" FT STRAND 601..603 FT /evidence="ECO:0007829|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 //