NRAM_I34A1
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 03-AUG-2022, entry version 153.
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.
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;
CC Evidence={ECO:0000255|HAMAP-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}.
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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 GeneID; 956530; -.
DR KEGG; vg:956530; -.
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:0016021; C:integral component of membrane; IEA:UniProtKB-UniRule.
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:0046730; P:induction by virus of host 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 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; SSF50939; 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
