NOTUM_MOUSE
ID NOTUM_MOUSE Reviewed; 503 AA.
AC Q8R116; A2ABZ5; A2ABZ6;
DT 26-FEB-2008, integrated into UniProtKB/Swiss-Prot.
DT 26-FEB-2008, sequence version 2.
DT 03-AUG-2022, entry version 120.
DE RecName: Full=Palmitoleoyl-protein carboxylesterase NOTUM {ECO:0000250|UniProtKB:Q6P988};
DE EC=3.1.1.98 {ECO:0000250|UniProtKB:Q6P988};
DE Flags: Precursor;
GN Name=Notum {ECO:0000312|MGI:MGI:1924833};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC STRAIN=FVB/N; TISSUE=Liver;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP PRELIMINARY FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=17967162; DOI=10.1042/bj20070511;
RA Traister A., Shi W., Filmus J.;
RT "Mammalian Notum induces the release of glypicans and other GPI-anchored
RT proteins from the cell surface.";
RL Biochem. J. 410:503-511(2008).
RN [4]
RP FUNCTION, AND MUTAGENESIS OF SER-239.
RX PubMed=25771893; DOI=10.1016/j.devcel.2015.02.014;
RA Zhang X., Cheong S.M., Amado N.G., Reis A.H., MacDonald B.T., Zebisch M.,
RA Jones E.Y., Abreu J.G., He X.;
RT "Notum is required for neural and head induction via Wnt deacylation,
RT oxidation, and inactivation.";
RL Dev. Cell 32:719-730(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. {ECO:0000269|PubMed:25771893}.
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:0000250|UniProtKB:Q9VUX3}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q8R116-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8R116-2; Sequence=VSP_031295, VSP_031296;
CC -!- TISSUE SPECIFICITY: Widely expressed. Expressed in lung, ovary, kidney,
CC liver and brain. Not detected in thymus, heart, spleen, stomach,
CC skeletal muscle and bone marrow. {ECO:0000269|PubMed:17967162}.
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. It was later reported to trigger glypican shedding,
CC by mediating cleavage of their GPI-anchor (PubMed:17967162). However,
CC while NOTUM specifically inhibit the Wnt signaling pathway, more
CC pleiotropic effects would be expected from an enzyme affecting
CC glypicans. It was finally shown that it requires glypicans to suppress
CC Wnt signaling, but does not cleave their GPI-anchor. It acts by
CC mediating depalmitoleoylation of WNT proteins, impairing WNT binding to
CC frizzled receptors. {ECO:0000269|PubMed:17967162, ECO:0000305}.
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DR EMBL; AL663030; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC025832; AAH25832.1; -; mRNA.
DR CCDS; CCDS49007.1; -. [Q8R116-1]
DR RefSeq; NP_780472.3; NM_175263.4. [Q8R116-1]
DR RefSeq; XP_011247616.1; XM_011249314.2.
DR AlphaFoldDB; Q8R116; -.
DR SMR; Q8R116; -.
DR STRING; 10090.ENSMUSP00000101784; -.
DR BindingDB; Q8R116; -.
DR ChEMBL; CHEMBL3758064; -.
DR ESTHER; mouse-notum; Pectinacetylesterase-Notum.
DR GlyGen; Q8R116; 1 site.
DR PhosphoSitePlus; Q8R116; -.
DR PaxDb; Q8R116; -.
DR PRIDE; Q8R116; -.
DR Antibodypedia; 19856; 156 antibodies from 28 providers.
DR DNASU; 77583; -.
DR Ensembl; ENSMUST00000106177; ENSMUSP00000101783; ENSMUSG00000042988. [Q8R116-1]
DR Ensembl; ENSMUST00000106178; ENSMUSP00000101784; ENSMUSG00000042988. [Q8R116-1]
DR GeneID; 77583; -.
DR KEGG; mmu:77583; -.
DR UCSC; uc007mty.2; mouse. [Q8R116-2]
DR UCSC; uc007mtz.2; mouse. [Q8R116-1]
DR CTD; 147111; -.
DR MGI; MGI:1924833; Notum.
DR VEuPathDB; HostDB:ENSMUSG00000042988; -.
DR eggNOG; KOG4287; Eukaryota.
DR GeneTree; ENSGT00390000015892; -.
DR HOGENOM; CLU_026533_1_1_1; -.
DR InParanoid; Q8R116; -.
DR OMA; ENCDTRY; -.
DR OrthoDB; 610784at2759; -.
DR PhylomeDB; Q8R116; -.
DR TreeFam; TF324830; -.
DR Reactome; R-MMU-381426; Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs).
DR Reactome; R-MMU-5362798; Release of Hh-Np from the secreting cell.
DR Reactome; R-MMU-8957275; Post-translational protein phosphorylation.
DR BioGRID-ORCS; 77583; 0 hits in 74 CRISPR screens.
DR PRO; PR:Q8R116; -.
DR Proteomes; UP000000589; Chromosome 11.
DR RNAct; Q8R116; protein.
DR Bgee; ENSMUSG00000042988; Expressed in gastrula and 90 other tissues.
DR ExpressionAtlas; Q8R116; baseline and differential.
DR Genevisible; Q8R116; MM.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0016298; F:lipase activity; IDA:MGI.
DR GO; GO:1990699; F:palmitoleyl hydrolase activity; IDA:UniProtKB.
DR GO; GO:0060348; P:bone development; IMP:MGI.
DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IDA:MGI.
DR GO; GO:0030178; P:negative regulation of Wnt signaling pathway; IDA:UniProtKB.
DR GO; GO:1990697; P:protein depalmitoleylation; IDA:UniProtKB.
DR GO; GO:0030500; P:regulation of bone mineralization; IDA:MGI.
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 Alternative splicing; Glycoprotein; Hydrolase; Phosphoprotein;
KW Reference proteome; Secreted; Serine esterase; Signal;
KW Wnt signaling pathway.
FT SIGNAL 1..19
FT /evidence="ECO:0000255"
FT CHAIN 20..503
FT /note="Palmitoleoyl-protein carboxylesterase NOTUM"
FT /id="PRO_0000318756"
FT REGION 23..53
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 31..46
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 239
FT /note="Charge relay system"
FT /evidence="ECO:0000305|PubMed:25771893"
FT ACT_SITE 347
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:Q6P988"
FT ACT_SITE 396
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:Q6P988"
FT MOD_RES 88
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q6P988"
FT CARBOHYD 103
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VAR_SEQ 1..175
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_031295"
FT VAR_SEQ 176..185
FT /note="NPHWWNANMV -> MVGSPDPCYS (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_031296"
FT MUTAGEN 239
FT /note="S->A: Abolishes enzyme activity. Unable to mediate
FT serine depalmitoleoylation of WNT proteins."
FT /evidence="ECO:0000269|PubMed:25771893"
FT CONFLICT 483
FT /note="T -> M (in Ref. 2; AAH25832)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 503 AA; 56584 MW; 9C92182D2F9DEDAF CRC64;
MGGEVRVLLL LGLLHWVGGS EGRKTWRRRG QQPPQPPPPP PLPQRAEVEP GAGQPVESFP
LDFTAVEGNM DSFMAQVKSL AQSLYPCSAQ QLNEDLRLHL LLNTSVTCND GSPAGYYLKE
SKGSRRWLLF LEGGWYCFNR ENCDSRYSTM RRLMSSKDWP HTRTGTGILS SQPEENPHWW
NANMVFIPYC SSDVWSGASP KSDKNEYAFM GSLIIQEVVR ELLGKGLSGA KVLLLAGSSA
GGTGVLLNVD RVAELLEELG YPSIQVRGLA DSGWFLDNKQ YRRSDCIDTI NCAPTDAIRR
GIRYWSGMVP ERCQRQFKEG EEWNCFFGYK VYPTLRCPVF VVQWLFDEAQ LTVDNVHLTG
QPVQEGQWLY IQNLGRELRG TLKDVQASFA PACLSHEIII RSYWTDVQVK GTSLPRALHC
WDRSFHDSHK ASKTPMKGCP FHLVDSCPWP HCNPSCPTIR DQFTGQEMNV AQFLMHMGFD
VQTVAQQQGM EPSKLLGMLS NGN
