ID NRAM_I18A0 Reviewed; 469 AA. AC Q9IGQ6; O10421; DT 13-NOV-2007, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-2000, sequence version 1. DT 24-JAN-2024, entry version 118. 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/Brevig Mission/1/1918 H1N1) (Influenza A virus OS (strain A/South Carolina/1/1918 H1N1)). OC Viruses; Riboviria; Orthornavirae; Negarnaviricota; Polyploviricotina; OC Insthoviricetes; Articulavirales; Orthomyxoviridae; Alphainfluenzavirus; OC Alphainfluenzavirus influenzae; Influenza A virus. OX NCBI_TaxID=88776; OH NCBI_TaxID=8782; Aves. OH NCBI_TaxID=9606; Homo sapiens (Human). OH NCBI_TaxID=9823; Sus scrofa (Pig). RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=10823895; DOI=10.1073/pnas.100140097; RA Reid A.H., Fanning T.G., Janczewski T.A., Taubenberger J.K.; RT "Characterization of the 1918 'Spanish' influenza virus neuraminidase RT gene."; RL Proc. Natl. Acad. Sci. U.S.A. 97:6785-6790(2000). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC RNA] OF 12-23. RC STRAIN=A/South Carolina/1/18; RX PubMed=9065404; DOI=10.1126/science.275.5307.1793; RA Taubenberger J.K., Reid A.H., Krafft A.E., Bijwaard K.E., Fanning T.G.; RT "Initial genetic characterization of the 1918 'Spanish' influenza virus."; RL Science 275:1793-1796(1997). RN [3] RP X-RAY CRYSTALLOGRAPHY (1.45 ANGSTROMS) OF 83-467 IN COMPLEX WITH CALCIUM RP AND INHIBITOR ZANAMIVIR, COFACTOR, SUBUNIT, GLYCOSYLATION AT ASN-146, AND RP DISULFIDE BOND. RX PubMed=18715929; DOI=10.1128/jvi.00959-08; RA Xu X., Zhu X., Dwek R.A., Stevens J., Wilson I.A.; RT "Structural characterization of the 1918 influenza virus H1N1 RT neuraminidase."; RL J. Virol. 82:10493-10501(2008). 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, ECO:0000269|PubMed:18715929}; CC Note=Binds 1 Ca(2+) ion per subunit. {ECO:0000269|PubMed:18715929}; 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 ECO:0000269|PubMed:18715929}. 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 ECO:0000269|PubMed:18715929}. 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 -!- MISCELLANEOUS: South Carolina isolate has been sequenced from formalid CC fixed-lung tissues of a 21-year-old male which died in 1918 at Ft. CC Jackson, SC. Brevig Mission isolate has been sequenced from lung CC tissues of an Inuit woman buried in the permafrost in a gravesite near CC Brevig Mission, Alaska. This sample was recovered by John Hultin, CC retired pathologist. 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; AF250356; AAF77036.1; -; mRNA. DR EMBL; U94893; AAC57065.1; -; Genomic_DNA. DR PDB; 3B7E; X-ray; 1.45 A; A/B=83-467. DR PDB; 3BEQ; X-ray; 1.64 A; A/B=83-467. DR PDB; 3CYE; X-ray; 1.65 A; A/B=83-469. DR PDB; 6D96; X-ray; 2.15 A; A/B/C/D/E/F/G/H=82-469. DR PDB; 6LXI; X-ray; 2.50 A; A/B=1-469. DR PDB; 8E6J; EM; 2.70 A; A/B/C/D=82-469. DR PDB; 8E6K; EM; 3.10 A; A/B/C/D=82-469. DR PDBsum; 3B7E; -. DR PDBsum; 3BEQ; -. DR PDBsum; 3CYE; -. DR PDBsum; 6D96; -. DR PDBsum; 6LXI; -. DR PDBsum; 8E6J; -. DR PDBsum; 8E6K; -. DR EMDB; EMD-27920; -. DR EMDB; EMD-27921; -. DR SMR; Q9IGQ6; -. DR BindingDB; Q9IGQ6; -. DR ChEMBL; CHEMBL1795169; -. DR DrugCentral; Q9IGQ6; -. DR CAZy; GH34; Glycoside Hydrolase Family 34. DR GlyCosmos; Q9IGQ6; 7 sites, No reported glycans. DR iPTMnet; Q9IGQ6; -. DR BRENDA; 3.2.1.18; 7479. DR SABIO-RK; Q9IGQ6; -. DR EvolutionaryTrace; Q9IGQ6; -. DR PRO; PR:Q9IGQ6; -. DR Proteomes; UP000008430; Genome. DR GO; GO:0020002; C:host cell plasma membrane; IEA:UniProtKB-SubCell. DR GO; GO:0016020; C:membrane; IEA:UniProtKB-UniRule. 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:0046872; F:metal ion binding; IEA:UniProtKB-UniRule. DR GO; GO:0005975; P:carbohydrate metabolic process; IEA:InterPro. DR GO; GO:0046761; P:viral budding from plasma membrane; IEA:UniProtKB-UniRule. 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 Signal-anchor; Transmembrane; Transmembrane helix; Virion. FT CHAIN 1..469 FT /note="Neuraminidase" FT /id="PRO_0000310569" 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..469 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..90 FT /note="Hypervariable stalk region" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT REGION 91..469 FT /note="Head of neuraminidase" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT ACT_SITE 151 FT /note="Proton donor/acceptor" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT ACT_SITE 402 FT /note="Nucleophile" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT BINDING 118 FT /ligand="substrate" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT BINDING 152 FT /ligand="substrate" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT BINDING 277..278 FT /ligand="substrate" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT BINDING 293 FT /ligand="substrate" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT BINDING 294 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071, FT ECO:0000269|PubMed:18715929" FT BINDING 298 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071, FT ECO:0000269|PubMed:18715929" FT BINDING 324 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071, FT ECO:0000269|PubMed:18715929" FT BINDING 344 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071, FT ECO:0000269|PubMed:18715929" FT BINDING 368 FT /ligand="substrate" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT CARBOHYD 50 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 63 FT /note="N-linked (GlcNAc...) asparagine; by host" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT CARBOHYD 68 FT /note="N-linked (GlcNAc...) asparagine; by host" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT CARBOHYD 88 FT /note="N-linked (GlcNAc...) asparagine; by host" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT CARBOHYD 146 FT /note="N-linked (GlcNAc...) asparagine; by host" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071, FT ECO:0000269|PubMed:18715929" FT CARBOHYD 235 FT /note="N-linked (GlcNAc...) asparagine; by host" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071" FT DISULFID 92..417 FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071, FT ECO:0000269|PubMed:18715929" FT DISULFID 124..129 FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071, FT ECO:0000269|PubMed:18715929" FT DISULFID 184..231 FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071, FT ECO:0000269|PubMed:18715929" FT DISULFID 233..238 FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071, FT ECO:0000269|PubMed:18715929" FT DISULFID 279..292 FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071, FT ECO:0000269|PubMed:18715929" FT DISULFID 281..290 FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071, FT ECO:0000269|PubMed:18715929" FT DISULFID 318..335 FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071, FT ECO:0000269|PubMed:18715929" FT DISULFID 421..446 FT /evidence="ECO:0000255|HAMAP-Rule:MF_04071, FT ECO:0000269|PubMed:18715929" FT STRAND 95..102 FT /evidence="ECO:0007829|PDB:3B7E" FT HELIX 105..109 FT /evidence="ECO:0007829|PDB:3B7E" FT STRAND 115..124 FT /evidence="ECO:0007829|PDB:3B7E" FT STRAND 129..142 FT /evidence="ECO:0007829|PDB:3B7E" FT HELIX 143..145 FT /evidence="ECO:0007829|PDB:3B7E" FT TURN 146..149 FT /evidence="ECO:0007829|PDB:3B7E" FT STRAND 157..162 FT /evidence="ECO:0007829|PDB:3B7E" FT TURN 169..171 FT /evidence="ECO:0007829|PDB:3B7E" FT STRAND 173..177 FT /evidence="ECO:0007829|PDB:3B7E" FT STRAND 179..185 FT /evidence="ECO:0007829|PDB:3B7E" FT STRAND 190..197 FT /evidence="ECO:0007829|PDB:3B7E" FT TURN 199..201 FT /evidence="ECO:0007829|PDB:6LXI" FT STRAND 203..208 FT /evidence="ECO:0007829|PDB:3B7E" FT STRAND 211..217 FT /evidence="ECO:0007829|PDB:3B7E" FT STRAND 219..222 FT /evidence="ECO:0007829|PDB:3B7E" FT STRAND 228..230 FT /evidence="ECO:0007829|PDB:3B7E" FT STRAND 232..234 FT /evidence="ECO:0007829|PDB:3B7E" FT STRAND 237..245 FT /evidence="ECO:0007829|PDB:3B7E" FT STRAND 247..249 FT /evidence="ECO:0007829|PDB:3B7E" FT STRAND 252..259 FT /evidence="ECO:0007829|PDB:3B7E" FT STRAND 262..268 FT /evidence="ECO:0007829|PDB:3B7E" FT STRAND 277..284 FT /evidence="ECO:0007829|PDB:3B7E" FT STRAND 287..293 FT /evidence="ECO:0007829|PDB:3B7E" FT TURN 295..297 FT /evidence="ECO:0007829|PDB:6D96" FT STRAND 302..306 FT /evidence="ECO:0007829|PDB:3B7E" FT STRAND 312..316 FT /evidence="ECO:0007829|PDB:3B7E" FT STRAND 324..326 FT /evidence="ECO:0007829|PDB:3B7E" FT STRAND 350..353 FT /evidence="ECO:0007829|PDB:3B7E" FT STRAND 356..361 FT /evidence="ECO:0007829|PDB:3B7E" FT STRAND 365..376 FT /evidence="ECO:0007829|PDB:3B7E" FT TURN 377..381 FT /evidence="ECO:0007829|PDB:3B7E" FT STRAND 388..399 FT /evidence="ECO:0007829|PDB:3B7E" FT STRAND 403..408 FT /evidence="ECO:0007829|PDB:3B7E" FT HELIX 410..413 FT /evidence="ECO:0007829|PDB:3B7E" FT STRAND 416..429 FT /evidence="ECO:0007829|PDB:3B7E" FT TURN 430..432 FT /evidence="ECO:0007829|PDB:3B7E" FT STRAND 433..436 FT /evidence="ECO:0007829|PDB:3B7E" FT STRAND 438..450 FT /evidence="ECO:0007829|PDB:3B7E" FT HELIX 466..468 FT /evidence="ECO:0007829|PDB:6LXI" SQ SEQUENCE 469 AA; 51406 MW; 28888692D4394159 CRC64; MNPNQKIITI GSICMVVGII SLILQIGNII SIWVSHSIQT GNQNHPETCN QSIITYENNT WVNQTYVNIS NTNVVAGQDA TSVILTGNSS LCPISGWAIY SKDNGIRIGS KGDVFVIREP FISCSHLECR TFFLTQGALL NDKHSNGTVK DRSPYRTLMS CPVGEAPSPY NSRFESVAWS ASACHDGMGW LTIGISGPDN GAVAVLKYNG IITDTIKSWR NNILRTQESE CACVNGSCFT IMTDGPSNGQ ASYKILKIEK GKVTKSIELN APNYHYEECS CYPDTGKVMC VCRDNWHGSN RPWVSFDQNL DYQIGYICSG VFGDNPRPND GTGSCGPVSS NGANGIKGFS FRYDNGVWIG RTKSTSSRSG FEMIWDPNGW TETDSSFSVR QDIVAITDWS GYSGSFVQHP ELTGLDCMRP CFWVELIRGQ PKENTIWTSG SSISFCGVNS DTVGWSWPDG AELPFSIDK //