ID NRAM_I34A1 Reviewed; 454 AA. AC P03468; A4GXH6; Q20N35; Q84043; Q8JUU4; DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot. DT 06-MAR-2007, sequence version 2. DT 08-NOV-2023, entry version 157. DE RecName: Full=Neuraminidase {ECO:0000255|HAMAP-Rule:MF_04071}; DE EC=3.2.1.18 {ECO:0000255|HAMAP-Rule:MF_04071}; GN Name=NA {ECO:0000255|HAMAP-Rule:MF_04071}; OS Influenza A virus (strain A/Puerto Rico/8/1934 H1N1). OC Viruses; Riboviria; Orthornavirae; Negarnaviricota; Polyploviricotina; OC Insthoviricetes; Articulavirales; Orthomyxoviridae; Alphainfluenzavirus; OC Alphainfluenzavirus influenzae; Influenza A virus. OX NCBI_TaxID=211044; OH NCBI_TaxID=8782; Aves. OH NCBI_TaxID=9606; Homo sapiens (Human). OH NCBI_TaxID=9823; Sus scrofa (Pig). RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC RNA]. RX PubMed=7010182; DOI=10.1038/290213a0; RA Fields S., Winter G., Brownlee G.G.; RT "Structure of the neuraminidase gene in human influenza virus A/PR/8/34."; RL Nature 290:213-217(1981). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC RNA]. RX PubMed=11779399; DOI=10.1098/rstb.2001.0979; RA Schickli J.H., Flandorfer A., Nakaya T., Martinez-Sobrido L., RA Garcia-Sastre A., Palese P.; RT "Plasmid-only rescue of influenza A virus vaccine candidates."; RL Philos. Trans. R. Soc. Lond., B, Biol. Sci. 356:1965-1973(2001). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC RNA], AND REVERSE GENETICS. RX PubMed=15163504; DOI=10.1016/j.virusres.2004.02.028; RA de Wit E., Spronken M.I.J., Bestebroer T.M., Rimmelzwaan G.F., RA Osterhaus A.D.M.E., Fouchier R.A.M.; RT "Efficient generation and growth of influenza virus A/PR/8/34 from eight RT cDNA fragments."; RL Virus Res. 103:155-161(2004). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC RNA]. RA Ghedin E., Spiro D., Miller N., Zaborsky J., Feldblyum T., Subbu V., RA Shumway M., Sparenborg J., Groveman L., Halpin R., Sitz J., Koo H., RA Salzberg S.L., Webster R.G., Hoffmann E., Krauss S., Naeve C., Bao Y., RA Bolotov P., Dernovoy D., Kiryutin B., Lipman D.J., Tatusova T.; RT "The NIAID influenza genome sequencing project."; RL Submitted (MAR-2006) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC RNA] OF 1-71. RX PubMed=6927853; DOI=10.1016/0042-6822(82)90162-3; RA Blok J., Air G.M.; RT "Sequence variation at the 3' end of the neuraminidase gene from 39 RT influenza type A viruses."; RL Virology 121:211-229(1982). RN [6] RP REVIEW. RX PubMed=15567494; DOI=10.1016/j.virusres.2004.08.012; RA Nayak D.P., Hui E.K., Barman S.; RT "Assembly and budding of influenza virus."; RL Virus Res. 106:147-165(2004). RN [7] RP REVIEW. RX PubMed=16192481; DOI=10.1056/nejmra050740; RA Moscona A.; RT "Neuraminidase inhibitors for influenza."; RL N. Engl. J. Med. 353:1363-1373(2005). RN [8] RP REVIEW. RX PubMed=15744059; DOI=10.1248/bpb.28.399; RA Suzuki Y.; RT "Sialobiology of influenza: molecular mechanism of host range variation of RT influenza viruses."; RL Biol. Pharm. Bull. 28:399-408(2005). CC -!- FUNCTION: Catalyzes the removal of terminal sialic acid residues from CC viral and cellular glycoconjugates. Cleaves off the terminal sialic CC acids on the glycosylated HA during virus budding to facilitate virus CC release. Additionally helps virus spread through the circulation by CC further removing sialic acids from the cell surface. These cleavages CC prevent self-aggregation and ensure the efficient spread of the progeny CC virus from cell to cell. Otherwise, infection would be limited to one CC round of replication. Described as a receptor-destroying enzyme because CC it cleaves a terminal sialic acid from the cellular receptors. May CC facilitate viral invasion of the upper airways by cleaving the sialic CC acid moieties on the mucin of the airway epithelial cells. Likely to CC plays a role in the budding process through its association with lipid CC rafts during intracellular transport. May additionally display a raft- CC association independent effect on budding. Plays a role in the CC determination of host range restriction on replication and virulence. CC Sialidase activity in late endosome/lysosome traffic seems to enhance CC virus replication. {ECO:0000255|HAMAP-Rule:MF_04071}. 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; Evidence={ECO:0000255|HAMAP- CC Rule:MF_04071}; CC -!- COFACTOR: CC Name=Ca(2+); Xref=ChEBI:CHEBI:29108; Evidence={ECO:0000255|HAMAP- CC Rule:MF_04071}; CC -!- ACTIVITY REGULATION: Inhibited by the neuraminidase inhibitors CC zanamivir (Relenza) and oseltamivir (Tamiflu). These drugs interfere CC with the release of progeny virus from infected cells and are effective CC against all influenza strains. Resistance to neuraminidase inhibitors CC is quite rare. {ECO:0000255|HAMAP-Rule:MF_04071}. CC -!- SUBUNIT: Homotetramer. {ECO:0000255|HAMAP-Rule:MF_04071}. CC -!- SUBCELLULAR LOCATION: Virion membrane {ECO:0000255|HAMAP- CC Rule:MF_04071}. Host apical cell membrane {ECO:0000255|HAMAP- CC Rule:MF_04071}; Single-pass type II membrane protein CC {ECO:0000255|HAMAP-Rule:MF_04071}. Note=Preferentially accumulates at CC the apical plasma membrane in infected polarized epithelial cells, CC which is the virus assembly site. Uses lipid rafts for cell surface CC transport and apical sorting. In the virion, forms a mushroom-shaped CC spike on the surface of the membrane. {ECO:0000255|HAMAP- CC Rule:MF_04071}. CC -!- DOMAIN: Intact N-terminus is essential for virion morphogenesis. CC Possesses two apical sorting signals, one in the ectodomain, which is CC likely to be a glycan, and the other in the transmembrane domain. The CC transmembrane domain also plays a role in lipid raft association. CC {ECO:0000255|HAMAP-Rule:MF_04071}. CC -!- PTM: N-glycosylated. {ECO:0000255|HAMAP-Rule:MF_04071}. CC -!- MISCELLANEOUS: The influenza A genome consist of 8 RNA segments. CC Genetic variation of hemagglutinin and/or neuraminidase genes results CC in the emergence of new influenza strains. The mechanism of variation CC can be the result of point mutations or the result of genetic CC reassortment between segments of two different strains. CC -!- SIMILARITY: Belongs to the glycosyl hydrolase 34 family. CC {ECO:0000255|HAMAP-Rule:MF_04071}. 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; J02146; AAA43412.1; -; Genomic_RNA. DR EMBL; AF389120; AAM75160.1; -; Genomic_RNA. DR EMBL; EF467823; ABO21711.1; -; Genomic_RNA. DR EMBL; CY009446; ABD77678.1; -; Genomic_RNA. DR EMBL; K01031; AAA43415.1; -; Genomic_RNA. DR RefSeq; NP_040981.1; NC_002018.1. DR PDB; 6WZY; X-ray; 1.50 A; C=181-190. DR PDB; 6X00; X-ray; 1.55 A; C=181-191. DR PDBsum; 6WZY; -. DR PDBsum; 6X00; -. DR SMR; P03468; -. DR IntAct; P03468; 20. DR BindingDB; P03468; -. DR ChEMBL; CHEMBL2051; -. DR DrugCentral; P03468; -. DR CAZy; GH34; Glycoside Hydrolase Family 34. DR GlyCosmos; P03468; 5 sites, No reported glycans. DR GeneID; 956530; -. DR KEGG; vg:956530; -. DR OrthoDB; 2789at10239; -. DR Reactome; R-HSA-168255; Influenza Infection. DR Reactome; R-HSA-168275; Entry of Influenza Virion into Host Cell via Endocytosis. DR Reactome; R-HSA-168277; Influenza Virus Induced Apoptosis. DR Reactome; R-HSA-168288; Fusion of the Influenza Virion to the Host Cell Endosome. DR Reactome; R-HSA-168298; Release. DR Reactome; R-HSA-168302; Budding. DR Reactome; R-HSA-168303; Packaging of Eight RNA Segments. DR Reactome; R-HSA-168316; Assembly of Viral Components at the Budding Site. DR Reactome; R-HSA-168336; Uncoating of the Influenza Virion. DR Reactome; R-HSA-168874; Transport of HA trimer, NA tetramer and M2 tetramer from the endoplasmic reticulum to the Golgi Apparatus. DR Reactome; R-HSA-192823; Viral mRNA Translation. DR SABIO-RK; P03468; -. DR PRO; PR:P03468; -. DR Proteomes; UP000009255; Genome. DR Proteomes; UP000116373; Genome. DR Proteomes; UP000170967; Genome. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. DR GO; GO:0020002; C:host cell plasma membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005886; C:plasma membrane; TAS:Reactome. DR GO; GO:0055036; C:virion membrane; IEA:UniProtKB-SubCell. DR GO; GO:0052794; F:exo-alpha-(2->3)-sialidase activity; IEA:UniProtKB-UniRule. DR GO; GO:0052795; F:exo-alpha-(2->6)-sialidase activity; IEA:UniProtKB-UniRule. DR GO; GO:0052796; F:exo-alpha-(2->8)-sialidase activity; IEA:UniProtKB-UniRule. DR GO; GO:0004308; F:exo-alpha-sialidase activity; TAS:Reactome. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-UniRule. DR GO; GO:0016504; F:peptidase activator activity; TAS:Reactome. DR GO; GO:0005975; P:carbohydrate metabolic process; IEA:InterPro. DR GO; GO:0006955; P:immune response; TAS:Reactome. DR GO; GO:0046761; P:viral budding from plasma membrane; IDA:UniProtKB. DR GO; GO:0019076; P:viral release from host cell; TAS:Reactome. DR CDD; cd15483; Influenza_NA; 1. DR Gene3D; 2.120.10.10; -; 1. DR HAMAP; MF_04071; INFV_NRAM; 1. DR InterPro; IPR001860; Glyco_hydro_34. DR InterPro; IPR033654; Sialidase_Influenza_A/B. DR InterPro; IPR036278; Sialidase_sf. DR Pfam; PF00064; Neur; 1. DR SUPFAM; SSF50939; Sialidases; 1. PE 1: Evidence at protein level; KW 3D-structure; Calcium; Disulfide bond; Glycoprotein; Glycosidase; KW Host cell membrane; Host membrane; Hydrolase; Membrane; Metal-binding; KW Reference proteome; Signal-anchor; Transmembrane; Transmembrane helix; KW Virion. FT CHAIN 1..454 FT /note="Neuraminidase" FT /id="PRO_0000078712" FT TOPO_DOM 1..6 FT /note="Intravirion" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT TRANSMEM 7..27 FT /note="Helical" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT TOPO_DOM 28..454 FT /note="Virion surface" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT REGION 11..33 FT /note="Involved in apical transport and lipid raft FT association" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT REGION 36..75 FT /note="Hypervariable stalk region" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT REGION 76..454 FT /note="Head of neuraminidase" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT ACT_SITE 136 FT /note="Proton donor/acceptor" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT ACT_SITE 387 FT /note="Nucleophile" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT BINDING 103 FT /ligand="substrate" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT BINDING 137 FT /ligand="substrate" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT BINDING 262..263 FT /ligand="substrate" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT BINDING 278 FT /ligand="substrate" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT BINDING 279 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT BINDING 283 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT BINDING 309 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT BINDING 329 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT BINDING 353 FT /ligand="substrate" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT CARBOHYD 44 FT /note="N-linked (GlcNAc...) asparagine; by host" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT CARBOHYD 58 FT /note="N-linked (GlcNAc...) asparagine; by host" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT CARBOHYD 73 FT /note="N-linked (GlcNAc...) asparagine; by host" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT CARBOHYD 131 FT /note="N-linked (GlcNAc...) asparagine; by host" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT CARBOHYD 220 FT /note="N-linked (GlcNAc...) asparagine; by host" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT DISULFID 77..402 FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT DISULFID 109..114 FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT DISULFID 169..216 FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT DISULFID 218..223 FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT DISULFID 264..277 FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT DISULFID 266..275 FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT DISULFID 303..320 FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT DISULFID 406..431 FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT CONFLICT 8 FT /note="I -> T (in Ref. 2; AAM75160)" FT CONFLICT 51 FT /note="Q -> H (in Ref. 5; AAA43415)" FT CONFLICT 128 FT /note="K -> R (in Ref. 1; AAA43412)" FT CONFLICT 131 FT /note="N -> S (in Ref. 3; ABO21711 and 4; ABD77678)" FT CONFLICT 314 FT /note="E -> K (in Ref. 1; AAA43412)" FT CONFLICT 403 FT /note="M -> I (in Ref. 1; AAA43412)" FT CONFLICT 451 FT /note="S -> T (in Ref. 1; AAA43412)" SQ SEQUENCE 454 AA; 50121 MW; 7C52E0A9FD93A98B CRC64; MNPNQKIITI GSICLVVGLI SLILQIGNII SIWISHSIQT GSQNHTGICN QNIITYKNST WVKDTTSVIL TGNSSLCPIR GWAIYSKDNS IRIGSKGDVF VIREPFISCS HLECRTFFLT QGALLNDKHS NGTVKDRSPY RALMSCPVGE APSPYNSRFE SVAWSASACH DGMGWLTIGI SGPDNGAVAV LKYNGIITET IKSWRKKILR TQESECACVN GSCFTIMTDG PSDGLASYKI FKIEKGKVTK SIELNAPNSH YEECSCYPDT GKVMCVCRDN WHGSNRPWVS FDQNLDYQIG YICSGVFGDN PRPEDGTGSC GPVYVDGANG VKGFSYRYGN GVWIGRTKSH SSRHGFEMIW DPNGWTETDS KFSVRQDVVA MTDWSGYSGS FVQHPELTGL DCMRPCFWVE LIRGRPKEKT IWTSASSISF CGVNSDTVDW SWPDGAELPF SIDK //