ID   NRAM_INBLE              Reviewed;         466 AA.
AC   P03474;
DT   21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT   21-JUL-1986, sequence version 1.
DT   08-NOV-2023, entry version 152.
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 B virus (strain B/Lee/1940).
OC   Viruses; Riboviria; Orthornavirae; Negarnaviricota; Polyploviricotina;
OC   Insthoviricetes; Articulavirales; Orthomyxoviridae; Betainfluenzavirus;
OC   Betainfluenzavirus influenzae; Influenza B virus.
OX   NCBI_TaxID=518987;
OH   NCBI_TaxID=9606; Homo sapiens (Human).
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RX   PubMed=6294654; DOI=10.1073/pnas.79.22.6817;
RA   Shaw M.W., Lamb R.A., Erickson B.W., Briedis D.J., Choppin P.W.;
RT   "Complete nucleotide sequence of the neuraminidase gene of influenza B
RT   virus.";
RL   Proc. Natl. Acad. Sci. U.S.A. 79:6817-6821(1982).
RN   [2]
RP   MUTAGENESIS OF GLU-117; ASP-149; ARG-150; ARG-223; GLU-275; ARG-374 AND
RP   TYR-409.
RX   PubMed=9874196; DOI=10.1046/j.1432-1327.1998.2580320.x;
RA   Ghate A.A., Air G.M.;
RT   "Site-directed mutagenesis of catalytic residues of influenza virus
RT   neuraminidase as an aid to drug design.";
RL   Eur. J. Biochem. 258:320-331(1998).
RN   [3]
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   [4]
RP   X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF 77-466 IN COMPLEX WITH SYNTHETIC
RP   INHIBITOR AND CALCIUM, SUBUNIT, COFACTOR, AND GLYCOSYLATION AT ASN-284.
RX   PubMed=7880809; DOI=10.1021/bi00010a003;
RA   Jedrzejas M.J., Singh S., Brouillette W.J., Laver W.G., Air G.M., Luo M.;
RT   "Structures of aromatic inhibitors of influenza virus neuraminidase.";
RL   Biochemistry 34:3144-3151(1995).
RN   [5]
RP   X-RAY CRYSTALLOGRAPHY (2.35 ANGSTROMS) OF 77-466 IN COMPLEX WITH SYNTHETIC
RP   INHIBITOR AND CALCIUM, SUBUNIT, AND COFACTOR.
RX   PubMed=10547289; DOI=10.1006/jmbi.1999.3180;
RA   Finley J.B., Atigadda V.R., Duarte F., Zhao J.J., Brouillette W.J.,
RA   Air G.M., Luo M.;
RT   "Novel aromatic inhibitors of influenza virus neuraminidase make selective
RT   interactions with conserved residues and water molecules in the active
RT   site.";
RL   J. Mol. Biol. 293:1107-1119(1999).
RN   [6]
RP   X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 78-466 IN COMPLEX WITH SYNTHETIC
RP   INHIBITOR, SUBUNIT, AND COFACTOR.
RX   PubMed=15159560; DOI=10.1107/s0907444904006225;
RA   Lommer B.S., Ali S.M., Bajpai S.N., Brouillette W.J., Air G.M., Luo M.;
RT   "A benzoic acid inhibitor induces a novel conformational change in the
RT   active site of Influenza B virus neuraminidase.";
RL   Acta Crystallogr. D 60:1017-1023(2004).
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:10547289,
CC         ECO:0000269|PubMed:15159560, ECO:0000269|PubMed:7880809};
CC       Note=Binds 1 Ca(2+) ion per subunit. {ECO:0000269|PubMed:10547289,
CC       ECO:0000269|PubMed:15159560, ECO:0000269|PubMed:7880809};
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:10547289, ECO:0000269|PubMed:15159560,
CC       ECO:0000269|PubMed:7880809}.
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:7880809}.
CC   -!- MISCELLANEOUS: The influenza B 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; J02095; AAA43749.1; -; Genomic_RNA.
DR   PIR; A00886; NMIV4.
DR   RefSeq; NP_056663.1; NC_002209.1.
DR   PDB; 1B9S; X-ray; 2.50 A; A=77-466.
DR   PDB; 1B9T; X-ray; 2.40 A; A=77-466.
DR   PDB; 1B9V; X-ray; 2.35 A; A=77-466.
DR   PDB; 1INF; X-ray; 2.40 A; A=77-466.
DR   PDB; 1INV; X-ray; 2.40 A; A=77-466.
DR   PDB; 1IVB; X-ray; 2.40 A; A=77-466.
DR   PDB; 1VCJ; X-ray; 2.40 A; A=78-466.
DR   PDBsum; 1B9S; -.
DR   PDBsum; 1B9T; -.
DR   PDBsum; 1B9V; -.
DR   PDBsum; 1INF; -.
DR   PDBsum; 1INV; -.
DR   PDBsum; 1IVB; -.
DR   PDBsum; 1VCJ; -.
DR   SMR; P03474; -.
DR   BindingDB; P03474; -.
DR   ChEMBL; CHEMBL3377; -.
DR   DrugBank; DB03475; 1-[4-Carboxy-2-(3-Pentylamino)Phenyl]-5,5'-Di(Hydroxymethyl)Pyrrolidin-2-One.
DR   DrugBank; DB03342; 4-(Acetylamino)-3-Guanidinobenzoic Acid.
DR   DrugBank; DB08570; 4-(ACETYLAMINO)-3-HYDROXY-5-NITROBENZOIC ACID.
DR   DrugBank; DB07762; 4-(N-ACETYLAMINO)-3-[N-(2-ETHYLBUTANOYLAMINO)]BENZOIC ACID.
DR   DrugCentral; P03474; -.
DR   CAZy; GH34; Glycoside Hydrolase Family 34.
DR   GlyCosmos; P03474; 4 sites, No reported glycans.
DR   GeneID; 26824004; -.
DR   KEGG; vg:26824004; -.
DR   OrthoDB; 2789at10239; -.
DR   SABIO-RK; P03474; -.
DR   EvolutionaryTrace; P03474; -.
DR   PRO; PR:P03474; -.
DR   Proteomes; UP000008158; 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   Gene3D; 2.120.10.10; -; 1.
DR   HAMAP; MF_04071; INFV_NRAM; 1.
DR   InterPro; IPR001860; Glyco_hydro_34.
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..466
FT                   /note="Neuraminidase"
FT                   /id="PRO_0000078732"
FT   TOPO_DOM        1..8
FT                   /note="Intravirion"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04071"
FT   TRANSMEM        9..31
FT                   /note="Helical"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04071"
FT   TOPO_DOM        32..466
FT                   /note="Virion surface"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04071"
FT   REGION          13..35
FT                   /note="Involved in apical transport and lipid raft
FT                   association"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04071"
FT   REGION          38..86
FT                   /note="Hypervariable stalk region"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04071"
FT   REGION          89..466
FT                   /note="Head of neuraminidase"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04071"
FT   ACT_SITE        149
FT                   /note="Proton donor/acceptor"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04071"
FT   ACT_SITE        409
FT                   /note="Nucleophile"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04071"
FT   BINDING         116
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04071"
FT   BINDING         150
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04071"
FT   BINDING         275..276
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04071"
FT   BINDING         292
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04071"
FT   BINDING         293
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04071,
FT                   ECO:0000269|PubMed:10547289, ECO:0000269|PubMed:7880809"
FT   BINDING         297
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /evidence="ECO:0000269|PubMed:10547289,
FT                   ECO:0000269|PubMed:7880809"
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:10547289, ECO:0000269|PubMed:7880809"
FT   BINDING         346
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /evidence="ECO:0000269|PubMed:10547289,
FT                   ECO:0000269|PubMed:7880809"
FT   BINDING         374
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04071"
FT   CARBOHYD        56
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04071"
FT   CARBOHYD        64
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04071"
FT   CARBOHYD        144
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04071"
FT   CARBOHYD        284
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04071"
FT   DISULFID        87..420
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04071"
FT   DISULFID        122..127
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04071"
FT   DISULFID        182..229
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04071"
FT   DISULFID        231..236
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04071"
FT   DISULFID        277..291
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04071"
FT   DISULFID        279..289
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04071"
FT   DISULFID        318..337
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04071"
FT   DISULFID        424..447
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04071"
FT   MUTAGEN         117
FT                   /note="E->G: Reduced substrate binding."
FT                   /evidence="ECO:0000269|PubMed:9874196"
FT   MUTAGEN         149
FT                   /note="D->E: Almost complete loss of enzymatic activity."
FT                   /evidence="ECO:0000269|PubMed:9874196"
FT   MUTAGEN         150
FT                   /note="R->K: Reduced substrate binding."
FT                   /evidence="ECO:0000269|PubMed:9874196"
FT   MUTAGEN         223
FT                   /note="R->K: Reduced substrate binding."
FT                   /evidence="ECO:0000269|PubMed:9874196"
FT   MUTAGEN         275
FT                   /note="E->D: Almost complete loss of enzymatic activity."
FT                   /evidence="ECO:0000269|PubMed:9874196"
FT   MUTAGEN         374
FT                   /note="R->K: 80% loss of catalytic efficiency."
FT                   /evidence="ECO:0000269|PubMed:9874196"
FT   MUTAGEN         374
FT                   /note="R->N: 94% loss of catalytic efficiency."
FT                   /evidence="ECO:0000269|PubMed:9874196"
FT   MUTAGEN         409
FT                   /note="Y->F: Complete loss of enzymatic activity."
FT                   /evidence="ECO:0000269|PubMed:9874196"
FT   STRAND          88..90
FT                   /evidence="ECO:0007829|PDB:1INV"
FT   STRAND          92..98
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   HELIX           100..102
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   STRAND          106..108
FT                   /evidence="ECO:0007829|PDB:1B9T"
FT   STRAND          119..122
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   STRAND          127..133
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   STRAND          137..139
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   TURN            144..147
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   STRAND          155..160
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   TURN            167..169
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   STRAND          171..175
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   STRAND          177..183
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   STRAND          185..195
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   TURN            197..199
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   STRAND          201..206
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   STRAND          209..215
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   STRAND          217..220
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   STRAND          226..228
FT                   /evidence="ECO:0007829|PDB:1IVB"
FT   STRAND          230..232
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   STRAND          235..241
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   STRAND          245..247
FT                   /evidence="ECO:0007829|PDB:1B9T"
FT   STRAND          251..257
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   STRAND          260..265
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   STRAND          268..270
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   STRAND          275..292
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   STRAND          294..296
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   STRAND          301..306
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   TURN            307..310
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   STRAND          311..316
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   STRAND          324..326
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   STRAND          352..356
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   STRAND          361..367
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   STRAND          369..385
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   TURN            387..389
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   STRAND          395..406
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   STRAND          410..416
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   STRAND          418..432
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   STRAND          435..437
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   STRAND          439..448
FT                   /evidence="ECO:0007829|PDB:1B9V"
FT   STRAND          450..452
FT                   /evidence="ECO:0007829|PDB:1B9V"
SQ   SEQUENCE   466 AA;  51442 MW;  E6FF3E634F132263 CRC64;
     MLPSTVQTLT LLLTSGGVLL SLYVSASLSY LLYSDVLLKF SSTKTTAPTM SLECTNASNA
     QTVNHSATKE MTFPPPEPEW TYPRLSCQGS TFQKALLISP HRFGEIKGNS APLIIREPFV
     ACGPKECRHF ALTHYAAQPG GYYNGTRKDR NKLRHLVSVK LGKIPTVENS IFHMAAWSGS
     ACHDGREWTY IGVDGPDNDA LVKIKYGEAY TDTYHSYAHN ILRTQESACN CIGGDCYLMI
     TDGSASGISK CRFLKIREGR IIKEILPTGR VEHTEECTCG FASNKTIECA CRDNSYTAKR
     PFVKLNVETD TAEIRLMCTK TYLDTPRPDD GSIAGPCESN GDKWLGGIKG GFVHQRMASK
     IGRWYSRTMS KTNRMGMELY VKYDGDPWTD SDALTLSGVM VSIEEPGWYS FGFEIKDKKC
     DVPCIGIEMV HDGGKDTWHS AATAIYCLMG SGQLLWDTVT GVDMAL
//