ID   NEUR3_RAT               Reviewed;         418 AA.
AC   Q99PW5; Q497C0;
DT   16-NOV-2001, integrated into UniProtKB/Swiss-Prot.
DT   01-JUN-2001, sequence version 1.
DT   24-JAN-2024, entry version 137.
DE   RecName: Full=Sialidase-3;
DE            EC=3.2.1.18 {ECO:0000250|UniProtKB:Q9UQ49};
DE   AltName: Full=Ganglioside sialidase;
DE   AltName: Full=Membrane sialidase;
DE   AltName: Full=N-acetyl-alpha-neuraminidase 3;
GN   Name=Neu3;
OS   Rattus norvegicus (Rat).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Rattus.
OX   NCBI_TaxID=10116;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RC   STRAIN=Sprague-Dawley; TISSUE=Brain;
RX   PubMed=11162581; DOI=10.1006/bbrc.2000.4186;
RA   Hasegawa T., Feijoo Carnero C., Wada T., Itoyama Y., Miyagi T.;
RT   "Differential expression of three sialidase genes in rat development.";
RL   Biochem. Biophys. Res. Commun. 280:726-732(2001).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Prostate;
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).
CC   -!- FUNCTION: Exo-alpha-sialidase that catalyzes the hydrolytic cleavage of
CC       the terminal sialic acid (N-acetylneuraminic acid, Neu5Ac) of a glycan
CC       moiety in the catabolism of glycolipids, glycoproteins and
CC       oligosacharides. Displays high catalytic efficiency for gangliosides
CC       including alpha-(2->3)-sialylated GD1a and GM3 and alpha-(2->8)-
CC       sialylated GD3. Plays a role in the regulation of transmembrane
CC       signaling through the modulation of ganglioside content of the lipid
CC       bilayer and by direct interaction with signaling receptors, such as
CC       EGFR. Desialylates EGFR and activates downstream signaling in
CC       proliferating cells. Contributes to clathrin-mediated endocytosis by
CC       regulating sorting of endocytosed receptors to early and recycling
CC       endosomes. {ECO:0000250|UniProtKB:Q9UQ49}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=Hydrolysis of alpha-(2->3)-, alpha-(2->6)-, alpha-
CC         (2->8)- glycosidic linkages of terminal sialic acid residues in
CC         oligosaccharides, glycoproteins, glycolipids, colominic acid and
CC         synthetic substrates.; EC=3.2.1.18;
CC         Evidence={ECO:0000250|UniProtKB:Q9UQ49};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a ganglioside GD1a + H2O = a ganglioside GM1 + N-
CC         acetylneuraminate; Xref=Rhea:RHEA:47832, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:35418, ChEBI:CHEBI:82637, ChEBI:CHEBI:82639;
CC         Evidence={ECO:0000250|UniProtKB:Q9UQ49};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:47833;
CC         Evidence={ECO:0000250|UniProtKB:Q9UQ49};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a ganglioside GD1a (d18:1(4E)) + H2O = a ganglioside GM1
CC         (d18:1(4E)) + N-acetylneuraminate; Xref=Rhea:RHEA:47856,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:35418, ChEBI:CHEBI:77709,
CC         ChEBI:CHEBI:78445; Evidence={ECO:0000250|UniProtKB:Q9UQ49};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:47857;
CC         Evidence={ECO:0000250|UniProtKB:Q9UQ49};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a ganglioside GD1b + H2O = a ganglioside GM1 + N-
CC         acetylneuraminate; Xref=Rhea:RHEA:47876, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:35418, ChEBI:CHEBI:82639, ChEBI:CHEBI:82939;
CC         Evidence={ECO:0000250|UniProtKB:Q9UQ49};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:47877;
CC         Evidence={ECO:0000250|UniProtKB:Q9UQ49};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a ganglioside GD1b (d18:1(4E)) + H2O = a ganglioside GM1
CC         (d18:1(4E)) + N-acetylneuraminate; Xref=Rhea:RHEA:48064,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:35418, ChEBI:CHEBI:77709,
CC         ChEBI:CHEBI:87785; Evidence={ECO:0000250|UniProtKB:Q9UQ49};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:48065;
CC         Evidence={ECO:0000250|UniProtKB:Q9UQ49};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a ganglioside GD3 + H2O = a ganglioside GM3 + N-
CC         acetylneuraminate; Xref=Rhea:RHEA:48120, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:35418, ChEBI:CHEBI:79210, ChEBI:CHEBI:79214;
CC         Evidence={ECO:0000250|UniProtKB:Q9UQ49};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:48121;
CC         Evidence={ECO:0000250|UniProtKB:Q9UQ49};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a ganglioside GD3 (d18:1(4E)) + H2O = a ganglioside GM3
CC         (d18:1(4E)) + N-acetylneuraminate; Xref=Rhea:RHEA:48124,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:35418, ChEBI:CHEBI:60065,
CC         ChEBI:CHEBI:78436; Evidence={ECO:0000250|UniProtKB:Q9UQ49};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:48125;
CC         Evidence={ECO:0000250|UniProtKB:Q9UQ49};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a ganglioside GM3 + H2O = a beta-D-galactosyl-(1->4)-beta-D-
CC         glucosyl-(1<->1)-ceramide + N-acetylneuraminate;
CC         Xref=Rhea:RHEA:48136, ChEBI:CHEBI:15377, ChEBI:CHEBI:35418,
CC         ChEBI:CHEBI:79208, ChEBI:CHEBI:79210;
CC         Evidence={ECO:0000250|UniProtKB:Q9UQ49};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:48137;
CC         Evidence={ECO:0000250|UniProtKB:Q9UQ49};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a ganglioside GM1 + H2O = a ganglioside GA1 + N-
CC         acetylneuraminate; Xref=Rhea:RHEA:47872, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:35418, ChEBI:CHEBI:82639, ChEBI:CHEBI:88069;
CC         Evidence={ECO:0000250|UniProtKB:Q9JMH7};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:47873;
CC         Evidence={ECO:0000250|UniProtKB:Q9JMH7};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a ganglioside GM1 (d18:1(4E)) + H2O = a ganglioside GA1
CC         (d18:1(4E)) + N-acetylneuraminate; Xref=Rhea:RHEA:48072,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:27938, ChEBI:CHEBI:35418,
CC         ChEBI:CHEBI:77709; Evidence={ECO:0000250|UniProtKB:Q9JMH7};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:48073;
CC         Evidence={ECO:0000250|UniProtKB:Q9JMH7};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a ganglioside GM2 (d18:1(4E)) + H2O = a ganglioside GA2
CC         (d18:1(4E)) + N-acetylneuraminate; Xref=Rhea:RHEA:48068,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:27731, ChEBI:CHEBI:35418,
CC         ChEBI:CHEBI:71502; Evidence={ECO:0000250|UniProtKB:Q9JMH7};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:48069;
CC         Evidence={ECO:0000250|UniProtKB:Q9JMH7};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a ganglioside GM3 (d18:1(4E)) + H2O = a beta-D-Gal-(1->4)-
CC         beta-D-Glc-(1<->1)-Cer(d18:1(4E)) + N-acetylneuraminate;
CC         Xref=Rhea:RHEA:47900, ChEBI:CHEBI:15377, ChEBI:CHEBI:17950,
CC         ChEBI:CHEBI:35418, ChEBI:CHEBI:60065;
CC         Evidence={ECO:0000250|UniProtKB:Q9UQ49};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:47901;
CC         Evidence={ECO:0000250|UniProtKB:Q9UQ49};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a ganglioside GT1b + H2O = a ganglioside GD1b + N-
CC         acetylneuraminate; Xref=Rhea:RHEA:47828, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:35418, ChEBI:CHEBI:82939, ChEBI:CHEBI:82940;
CC         Evidence={ECO:0000250|UniProtKB:O97859};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:47829;
CC         Evidence={ECO:0000250|UniProtKB:O97859};
CC   -!- SUBUNIT: Interacts with CAV1; this interaction enhances NEU3 sialidase
CC       activity within caveola. Interacts with EGFR; this interaction mediates
CC       desialylation of EGFR enhancing downstream signaling.
CC       {ECO:0000250|UniProtKB:Q9UQ49}.
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:Q9UQ49};
CC       Peripheral membrane protein {ECO:0000250|UniProtKB:Q9UQ49}. Membrane,
CC       caveola {ECO:0000250|UniProtKB:Q9UQ49}. Early endosome membrane
CC       {ECO:0000250|UniProtKB:Q9UQ49}; Peripheral membrane protein
CC       {ECO:0000250|UniProtKB:Q9UQ49}. Recycling endosome membrane
CC       {ECO:0000250|UniProtKB:Q9UQ49}; Peripheral membrane protein
CC       {ECO:0000250|UniProtKB:Q9UQ49}. Lysosome membrane
CC       {ECO:0000250|UniProtKB:Q9UQ49}; Peripheral membrane protein
CC       {ECO:0000250|UniProtKB:Q9UQ49}. Note=Associates with the external
CC       leaflet of the plasma membrane (By similarity). S-acylated NEU3 likely
CC       spans the lipid bilayer with a portion of C-terminus exposed to cytosol
CC       and the catalytic region facing the extracellular space (By
CC       similarity). {ECO:0000250|UniProtKB:Q9JMH7,
CC       ECO:0000250|UniProtKB:Q9UQ49}.
CC   -!- TISSUE SPECIFICITY: Expressed in brain, cardiac muscle and weakly in
CC       liver. {ECO:0000269|PubMed:11162581}.
CC   -!- PTM: Palmitoylated; may regulate intracellular trafficking and
CC       anchorage to plasma membrane and endomembranes.
CC       {ECO:0000250|UniProtKB:Q9UQ49}.
CC   -!- SIMILARITY: Belongs to the glycosyl hydrolase 33 family. {ECO:0000305}.
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DR   EMBL; AB026841; BAB32440.1; -; mRNA.
DR   EMBL; BC100625; AAI00626.1; -; mRNA.
DR   PIR; JC7588; JC7588.
DR   RefSeq; NP_446462.1; NM_054010.1.
DR   RefSeq; XP_008757887.1; XM_008759665.2.
DR   AlphaFoldDB; Q99PW5; -.
DR   SMR; Q99PW5; -.
DR   STRING; 10116.ENSRNOP00000024420; -.
DR   CAZy; GH33; Glycoside Hydrolase Family 33.
DR   PhosphoSitePlus; Q99PW5; -.
DR   SwissPalm; Q99PW5; -.
DR   PaxDb; 10116-ENSRNOP00000024420; -.
DR   Ensembl; ENSRNOT00000024420.6; ENSRNOP00000024420.2; ENSRNOG00000018106.6.
DR   Ensembl; ENSRNOT00055053591; ENSRNOP00055044316; ENSRNOG00055030888.
DR   Ensembl; ENSRNOT00060004535; ENSRNOP00060003229; ENSRNOG00060002817.
DR   Ensembl; ENSRNOT00065040666; ENSRNOP00065033157; ENSRNOG00065023750.
DR   GeneID; 117185; -.
DR   KEGG; rno:117185; -.
DR   UCSC; RGD:619881; rat.
DR   AGR; RGD:619881; -.
DR   CTD; 10825; -.
DR   RGD; 619881; Neu3.
DR   eggNOG; ENOG502QSFT; Eukaryota.
DR   GeneTree; ENSGT00950000182944; -.
DR   HOGENOM; CLU_024620_2_1_1; -.
DR   InParanoid; Q99PW5; -.
DR   OMA; ECGIKRE; -.
DR   OrthoDB; 5482010at2759; -.
DR   PhylomeDB; Q99PW5; -.
DR   TreeFam; TF331063; -.
DR   Reactome; R-RNO-4085001; Sialic acid metabolism.
DR   Reactome; R-RNO-9840310; Glycosphingolipid catabolism.
DR   PRO; PR:Q99PW5; -.
DR   Proteomes; UP000002494; Chromosome 1.
DR   Bgee; ENSRNOG00000018106; Expressed in skeletal muscle tissue and 19 other cell types or tissues.
DR   GO; GO:0005901; C:caveola; IEA:UniProtKB-SubCell.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR   GO; GO:0031901; C:early endosome membrane; ISO:RGD.
DR   GO; GO:0009897; C:external side of plasma membrane; ISO:RGD.
DR   GO; GO:0005765; C:lysosomal membrane; ISO:RGD.
DR   GO; GO:0005764; C:lysosome; IBA:GO_Central.
DR   GO; GO:0016020; C:membrane; IBA:GO_Central.
DR   GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR   GO; GO:0055038; C:recycling endosome membrane; ISO:RGD.
DR   GO; GO:0016997; F:alpha-sialidase activity; ISO:RGD.
DR   GO; GO:0052794; F:exo-alpha-(2->3)-sialidase activity; ISS:UniProtKB.
DR   GO; GO:0052795; F:exo-alpha-(2->6)-sialidase activity; IEA:UniProtKB-EC.
DR   GO; GO:0052796; F:exo-alpha-(2->8)-sialidase activity; ISS:UniProtKB.
DR   GO; GO:0004308; F:exo-alpha-sialidase activity; ISO:RGD.
DR   GO; GO:0005975; P:carbohydrate metabolic process; ISO:RGD.
DR   GO; GO:0006689; P:ganglioside catabolic process; ISS:UniProtKB.
DR   GO; GO:1900186; P:negative regulation of clathrin-dependent endocytosis; ISO:RGD.
DR   GO; GO:0009313; P:oligosaccharide catabolic process; ISO:RGD.
DR   GO; GO:0045742; P:positive regulation of epidermal growth factor receptor signaling pathway; ISO:RGD.
DR   CDD; cd15482; Sialidase_non-viral; 1.
DR   Gene3D; 2.120.10.10; -; 1.
DR   InterPro; IPR011040; Sialidase.
DR   InterPro; IPR026856; Sialidase_fam.
DR   InterPro; IPR036278; Sialidase_sf.
DR   PANTHER; PTHR10628; SIALIDASE; 1.
DR   PANTHER; PTHR10628:SF23; SIALIDASE-3; 1.
DR   Pfam; PF13088; BNR_2; 1.
DR   SUPFAM; SSF50939; Sialidases; 1.
DR   Genevisible; Q99PW5; RN.
PE   2: Evidence at transcript level;
KW   Carbohydrate metabolism; Cell membrane; Endosome; Glycosidase; Hydrolase;
KW   Lipid degradation; Lipid metabolism; Lipoprotein; Lysosome; Membrane;
KW   Reference proteome; Repeat.
FT   CHAIN           1..418
FT                   /note="Sialidase-3"
FT                   /id="PRO_0000208905"
FT   REPEAT          129..140
FT                   /note="BNR 1"
FT   REPEAT          201..212
FT                   /note="BNR 2"
FT   REPEAT          252..263
FT                   /note="BNR 3"
FT   MOTIF           24..27
FT                   /note="FRIP motif"
FT   ACT_SITE        50
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000250"
FT   ACT_SITE        369
FT                   /note="Nucleophile"
FT                   /evidence="ECO:0000250"
FT   ACT_SITE        386
FT                   /evidence="ECO:0000255"
FT   BINDING         25
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250"
FT   BINDING         45
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250"
FT   BINDING         179
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250"
FT   BINDING         181
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250"
FT   BINDING         223
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250"
FT   BINDING         243
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000255"
FT   BINDING         339
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250"
SQ   SEQUENCE   418 AA;  46980 MW;  7CC46F2E5952E240 CRC64;
     MEEVSSCSLR STLFQQEEQN RITYRIPALL YIPPTHTFLA FAEMRTSSRD EDAVYLVFRR
     GVMKGCSVEW GPQQPLMEAT LPGHRTMSPC PVWEKNTGRV YLFFICVQGH VSERWQLLWG
     RNAARLCFLY SEDSGCSWGE VKDLTEEVVG SEMKHWATFA VGPGHGIQLQ SGRLLIPAYA
     YLISCWFLCF PCSVKPHSLM FYSDDLGVTW HCGKFIKPQV TGECQVAEVP GKAGNLVLYC
     SARTPNKFRA EAFSTDSGDC FQKPTLNQQL CEPRGGCQGS VVSTRPLKMP YTCQDSSGKD
     VPSTQKCPLM DRSLEVEEGA GAPSGTWLLY SHPTNKKKRM NLGIYYNQNP LEVNYWSRPW
     ILNRGPSGYS DLAVVEGQGL FACLFECGER HEDEKIDFCL FSDQEVLSCD DCTSPSSN
//