NRAM_INBLE
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 03-AUG-2022, entry version 147.
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.
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 Note=Binds 1 Ca(2+) ion per subunit. {ECO:0000269|PubMed:10547289,
CC ECO:0000269|PubMed:15159560, ECO:0000269|PubMed:7880809};
CC -!- COFACTOR:
CC Name=Ca(2+); Xref=ChEBI:CHEBI:29108;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_04071,
CC ECO:0000269|PubMed:10547289, ECO:0000269|PubMed:15159560,
CC 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 PRIDE; P03474; -.
DR GeneID; 26824004; -.
DR KEGG; vg:26824004; -.
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:0016021; C:integral component of 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 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; 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..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
