NOTUM_DROME
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 03-AUG-2022, entry version 136.
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 AlphaFoldDB; Q9VUX3; -.
DR SMR; Q9VUX3; -.
DR DIP; DIP-61510N; -.
DR IntAct; Q9VUX3; 2.
DR STRING; 7227.FBpp0075193; -.
DR ESTHER; drome-q9vux3; Pectinacetylesterase-Notum.
DR GlyGen; Q9VUX3; 4 sites.
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 VEuPathDB; VectorBase:FBgn0044028; -.
DR eggNOG; KOG4287; Eukaryota.
DR GeneTree; ENSGT00940000173033; -.
DR HOGENOM; CLU_026533_1_1_1; -.
DR InParanoid; Q9VUX3; -.
DR OMA; FYLRKQP; -.
DR OrthoDB; 610784at2759; -.
DR PhylomeDB; Q9VUX3; -.
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 saliva-secreting gland and 2 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"
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
