Reviewed, UniProtKB/Swiss-Prot P03472 (NRAM_I75A5)

Names and origin

Protein names

Neuraminidase
Also known as:
     EC 3.2.1.18

Gene names

Name:

NA

Organism

Influenza A virus (strain A/Tern/Australia/G70C/1975 H11N9)

Taxonomic identifier

384509 [NCBI]

Taxonomic lineage

Viruses › ssRNA negative-strand viruses › Orthomyxoviridae › Influenzavirus A

Virus host

Aves [TaxID: 8782]

Protein existence

Evidence at protein level.

General annotation (Comments)

Function	Catalyzes the removal of terminal sialic acid residues from viral and cellular glycoconjugates. Cleaves off the terminal sialic acids on the glycosylated HA during virus budding to facilitate virus release. Additionally helps virus spread through the circulation by further removing sialic acids from the cell surface. These cleavages prevent self-aggregation and ensure the efficient spread of the progeny virus from cell to cell. Otherwise, infection would be limited to one round of replication. Described as a receptor-destroying enzyme because it cleaves a terminal sialic acid from the cellular receptors. May facilitate viral invasion of the upper airways by cleaving the sialic acid moities on the mucin of the airway epithelial cells. Likely to plays a role in the budding process through its association with lipid rafts during intracellular transport. May additionally display a raft-association independent effect on budding. Plays a role in the determination of host range restriction on replication and virulence. Sialidase activity in late endosome/lysosome traffic seems to enhance virus replication.
Catalytic activity	Hydrolysis of alpha-(2->3)-, alpha-(2->6)-, alpha-(2->8)- glycosidic linkages of terminal sialic acid residues in oligosaccharides, glycoproteins, glycolipids, colominic acid and synthetic substrates.
Cofactor	Binds 1 calcium ion By similarity.
Enzyme regulation	Inhibited by the neuraminidase inhibitors zanamivir (Relenza) and oseltamivir (Tamiflu). These drugs interfere with the release of progeny virus from infected cells and are effective against all influenza strains. Resistance to neuraminidase inhibitors is quite rare.
Subunit structure	Homotetramer By similarity.
Subcellular location	Virion membrane By similarity. Apical cell membrane; Single-pass type II membrane protein By similarity. Note=Preferentially accumulates at the apical plasma membrane in infected polarized epithelial cells, which is the virus assembly site. Uses lipid rafts for cell surface transport and apical sorting. In the virion, forms a mushroom-shaped spike on the surface of the membrane By similarity.
Domain	Intact N-terminus is essential for virion morphogenesis. Possess two apical sorting signals, one in the ectodomain, which is likely to be a glycan, and the other in the transmembrane domain. The transmembrane domain also plays a role in lipid raft association By similarity.
Post-translational modification	N-glycosylated By similarity.
Miscellaneous	The influenza A genome consist of 8 RNA segments. Genetic variation of hemagglutinin and/or neuraminidase genes results in the emergence of new influenza strains. The mechanism of variation can be the result of point mutations or the result of genetic reassortment between segments of two different strains.
Sequence similarities	Belongs to the glycosyl hydrolase 34 family.

Ontologies

Keywords
Cellular component	Membrane Virion
Domain	Signal-anchor Transmembrane
Ligand	Calcium Metal-binding
Molecular function	Glycosidase Hydrolase
PTM	Glycoprotein
Technical term	3D-structure
Gene Ontology (GO)
Cellular component	apical plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell virion membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Molecule processing

Chain

1 – 470

470

Neuraminidase

Regions

Topological domain

1 – 6

6

Cytoplasmic Potential

Transmembrane

7 – 35

29

Signal-anchor for type II membrane protein Potential

Topological domain

36 – 470

435

Extracellular Potential

Region

11 – 33

23

Involved in apical transport and lipid raft association By similarity

Region

36 – 91

56

Hypervariable stalk region

Region

92 – 470

379

Head of neuraminidase

Compositional bias

345 – 348

4

Poly-Asn

Sites

Active site

152

1

Potential

Active site

278

1

Potential

Active site

406

1

Potential

Metal binding

295

1

Calcium (via carbonyl oxygen) By similarity

Metal binding

299

1

Calcium (via carbonyl oxygen) By similarity

Metal binding

326

1

Calcium By similarity

Metal binding

348

1

Calcium (via carbonyl oxygen) By similarity

Binding site

119

1

Substrate Potential

Binding site

294

1

Substrate Potential

Binding site

372

1

Substrate Potential

Amino acid modifications

Glycosylation

63

1

N-linked (GlcNAc...) Potential

Glycosylation

66

1

N-linked (GlcNAc...) Potential

Glycosylation

87

1

N-linked (GlcNAc...)

Glycosylation

147

1

N-linked (GlcNAc...)

Glycosylation

202

1

N-linked (GlcNAc...)

Disulfide bond

93 ↔ 419

Disulfide bond

125 ↔ 130

Disulfide bond

177 ↔ 195

Disulfide bond

185 ↔ 232

Disulfide bond

234 ↔ 239

Disulfide bond

280 ↔ 293

Disulfide bond

282 ↔ 291

Disulfide bond

320 ↔ 338

Disulfide bond

423 ↔ 449

Experimental info

Sequence conflict

377

1

M → I in AAA43574. Ref.2

Sequence conflict

387 – 388

2

DK → ER in AAA43574. Ref.2

Secondary structure

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470

Helix Strand Turn

Details...

Beta strand

96 – 103

8

Helix

106 – 110

5

Beta strand

115 – 126

12

Beta strand

129 – 143

15

Helix

144 – 146

3

Turn

147 – 150

4

Beta strand

158 – 163

6

Turn

170 – 172

3

Beta strand

174 – 186

13

Beta strand

188 – 198

11

Beta strand

204 – 209

6

Beta strand

212 – 218

7

Beta strand

220 – 223

4

Beta strand

238 – 246

9

Beta strand

248 – 250

3

Beta strand

252 – 260

9

Beta strand

263 – 269

7

Beta strand

281 – 285

5

Beta strand

288 – 292

5

Beta strand

303 – 308

6

Turn

309 – 312

4

Beta strand

313 – 318

6

Beta strand

321 – 323

3

Beta strand

326 – 328

3

Beta strand

338 – 340

3

Beta strand

362 – 365

4

Beta strand

369 – 379

11

Turn

381 – 385

5

Beta strand

392 – 403

12

Beta strand

407 – 411

5

Beta strand

416 – 420

5

Beta strand

422 – 431

10

Turn

432 – 434

3

Beta strand

441 – 453

13

Helix

466 – 469

4

Sequences

	Sequence		Length	Mass (Da)
	P03472-1 [UniParc]. Last modified July 21, 1986. Version 1. Checksum: F114226CF93E1370	FASTA	470	52,469
	10 20 30 40 50 60 MNPNQKILCT SATALVIGTI AVLIGITNLG LNIGLHLKPS CNCSHSQPEA TNASQTIINN 70 80 90 100 110 120 YYNDTNITQI SNTNIQVEER AIRDFNNLTK GLCTINSWHI YGKDNAVRIG EDSDVLVTRE 130 140 150 160 170 180 PYVSCDPDEC RFYALSQGTT IRGKHSNGTI HDRSQYRALI SWPLSSPPTV YNSRVECIGW 190 200 210 220 230 240 SSTSCHDGKT RMSICISGPN NNASAVIWYN RRPVTEINTW ARNILRTQES ECVCHNGVCP 250 260 270 280 290 300 VVFTDGSATG PAETRIYYFK EGKILKWEPL AGTAKHIEEC SCYGERAEIT CTCRDNWQGS 310 320 330 340 350 360 NRPVIRIDPV AMTHTSQYIC SPVLTDNPRP NDPTVGKCND PYPGNNNNGV KGFSYLDGVN 370 380 390 400 410 420 TWLGRTISIA SRSGYEMLKV PNALTDDKSK PTQGQTIVLN TDWSGYSGSF MDYWAEGECY 430 440 450 460 470 RACFYVELIR GRPKEDKVWW TSNSIVSMCS STEFLGQWDW PDGAKIEYFL

References

[1]	"Gene and protein sequence of an influenza neuraminidase with hemagglutinin activity." Air G.M., Ritchie L.R., Laver W.G., Colman P.M. Virology 145:117-122(1985) [PubMed: 4013081] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC RNA].
[2]	"Distribution of sequence differences in influenza N9 neuraminidase of tern and whale viruses and crystallization of the whale neuraminidase complexed with antibodies." Air G.M., Webster R.G., Colman P.M., Laver W.G. Virology 160:346-354(1987) [PubMed: 3660585] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC RNA].
[3]	"Assembly and budding of influenza virus." Nayak D.P., Hui E.K., Barman S. Virus Res. 106:147-165(2004) [PubMed: 15567494] [Abstract] Cited for: REVIEW.
[4]	"Neuraminidase inhibitors for influenza." Moscona A. N. Engl. J. Med. 353:1363-1373(2005) [PubMed: 16192481] [Abstract] Cited for: REVIEW.
[5]	"Sialobiology of influenza: molecular mechanism of host range variation of influenza viruses." Suzuki Y. Biol. Pharm. Bull. 28:399-408(2005) [PubMed: 15744059] [Abstract] Cited for: REVIEW.
[6]	"Three-dimensional structure of neuraminidase of subtype N9 from an avian influenza virus." Baker A.T., Varghese J.N., Laver W.G., Air G.M., Colman P.M. Proteins 2:111-117(1987) [PubMed: 3447170] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 83-470.
[7]	"Three-dimensional structure of influenza A N9 neuraminidase and its complex with the inhibitor 2-deoxy 2,3-dehydro-N-acetyl neuraminic acid." Bossart-Whitaker P., Carson M., Babu Y.S., Smith C.D., Laver W.G., Air G.M. J. Mol. Biol. 232:1069-1083(1993) [PubMed: 8371267] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 83-470.
[8]	"Structural evidence for a second sialic acid binding site in avian influenza virus neuraminidases." Varghese J.N., Colman P.M., van Donkelaar A., Blick T.J., Sahasrabudhe A., McKimm-Breschkin J.L. Proc. Natl. Acad. Sci. U.S.A. 94:11808-11812(1997) [PubMed: 9342319] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 83-470.

Cross-references

Sequence databases

EMBLGenBankDDBJ

M11445 Genomic RNA. Translation: AAA43353.1.
M17813 Genomic RNA. Translation: AAA43574.1.

PIR

NMIV9. A00884.

3D structure databases

PDBMSD

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1A14	X-ray	2.50	N	83-470	[»]
1BJI	X-ray	2.00	A	83-470	[»]
1F8B	X-ray	1.80	A	83-470	[»]
1F8C	X-ray	1.70	A	83-470	[»]
1F8D	X-ray	1.40	A	83-470	[»]
1F8E	X-ray	1.40	A	83-470	[»]
1INY	X-ray	2.40	A	83-470	[»]
1L7F	X-ray	1.80	A	83-470	[»]
1L7G	X-ray	1.85	A	83-470	[»]
1L7H	X-ray	1.85	A	83-470	[»]
1MWE	X-ray	1.70	A	83-470	[»]
1NCA	X-ray	2.50	N	82-470	[»]
1NCB	X-ray	2.50	N	82-470	[»]
1NCC	X-ray	2.50	N	82-470	[»]
1NMC	X-ray	2.50	A/N	83-470	[»]
1NNA	X-ray	2.50	A	84-470	[»]
1NNB	X-ray	2.80	A	84-470	[»]
1NNC	X-ray	1.80	A	83-470	[»]
1XOE	X-ray	2.20	A	84-470	[»]