P06821 (M2_I34A1) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Matrix protein 2

Alternative name(s):
Proton channel protein M2

Gene names

Name:

M

Organism

Influenza A virus (strain A/Puerto Rico/8/1934 H1N1) [Reference proteome]

Taxonomic identifier

211044 [NCBI]

Taxonomic lineage

Viruses › ssRNA viruses › ssRNA negative-strand viruses › Orthomyxoviridae › Influenzavirus A › Influenza A virus › H1N1 subtype

Virus host

Aves [TaxID: 8782]
Homo sapiens (Human) [TaxID: 9606]
Sus scrofa (Pig) [TaxID: 9823]

Protein attributes

Sequence length	97 AA.
Sequence status	Complete.
Protein existence	Inferred from homology

General annotation (Comments)

Function	Forms a proton-selective ion channel that is necessary for the efficient release of the viral genome during virus entry. After attaching to the cell surface, the virion enters the cell by endocytosis. Acidification of the endosome triggers M2 ion channel activity. The influx of protons into virion interior is believed to disrupt interactions between the viral ribonucleoprotein (RNP), matrix protein 1 (M1), and lipid bilayers, thereby freeing the viral genome from interaction with viral proteins and enabling RNA segments to migrate to the host cell nucleus, where influenza virus RNA transcription and replication occur. Also plays a role in viral proteins secretory pathway. Elevates the intravesicular pH of normally acidic compartments, such as trans-Golgi network, preventing newly formed hemagglutinin from premature switching to the fusion-active conformation By similarity.
Enzyme regulation	The M2 protein from most influenza A strains is inhibited by amantadine and rimantadine, resulting in viral uncoating incapacity. Emergence of amantadine-resistant variants is usually rapid.
Subunit structure	Homotetramer; composed of two disulfide-linked dimers held together by non-covalent interactions. May interact with matrix protein 1 By similarity.
Subcellular location	Virion membrane By similarity. Host apical cell membrane; Single-pass type III membrane protein By similarity. Note: Abundantly expressed at the apical plasma membrane in infected polarized epithelial cells, in close proximity to budding and assembled virions. Minor component of virions (only 16-20 molecules/virion) By similarity.
Domain	Cytoplasmic tail plays an important role in virion assembly and morphogenesis By similarity.
Miscellaneous	When the channel is activated, one or more imidazole moities of His-37 probably become bi-protonated.
Sequence similarities	Belongs to the influenza viruses matrix protein M2 family.

Ontologies

Keywords
Biological process	Host-virus interaction Hydrogen ion transport Inhibition of host autophagy by virus Ion transport Transport
Cellular component	Host cell membrane Host membrane Membrane Virion
Coding sequence diversity	Alternative splicing
Domain	Signal-anchor Transmembrane Transmembrane helix
Molecular function	Ion channel Viral ion channel
PTM	Disulfide bond Glycoprotein Lipoprotein Palmitate Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	intracellular transport of viral proteins in host cell Traceable author statement. Source: Reactome suppression by virus of host autophagy Inferred from electronic annotation. Source: UniProtKB-KW uncoating of virus Traceable author statement. Source: Reactome viral entry into host cell via membrane fusion with the plasma membrane Traceable author statement. Source: Reactome viral entry into host cell via receptor-mediated endocytosis Traceable author statement. Source: Reactome viral genome packaging Traceable author statement. Source: Reactome viral release from host cell Traceable author statement. Source: Reactome viral transcription Traceable author statement. Source: Reactome
Cellular_component	Golgi membrane Traceable author statement. Source: Reactome cytosol Traceable author statement. Source: Reactome endocytic vesicle membrane Traceable author statement. Source: Reactome endoplasmic reticulum membrane Traceable author statement. Source: Reactome endosome lumen Traceable author statement. Source: Reactome host cell plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW plasma membrane Traceable author statement. Source: Reactome virion membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	hydrogen ion transmembrane transporter activity Inferred from electronic annotation. Source: InterPro transporter activity Traceable author statement. Source: Reactome
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Note: Only the first 9 residues are shared by the 2 isoforms.

Isoform M2 (identifier: P06821-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform M1 (identifier: P03485-1)

The sequence of this isoform can be found in the external entry P03485.
Isoforms of the same protein are often annotated in two different entries if their sequences differ significantly.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 97	97	Matrix protein 2		PRO_0000078890
Regions
	Topological domain	1 – 22	22	Virion surface Potential
	Transmembrane	23 – 43	21	Helical; Signal-anchor for type III membrane protein; Potential
	Topological domain	44 – 97	54	Intravirion Potential
Sites
	Site	37	1	Essential for channel activity, possibly by being protonated during channel activation, and by forming the channel gate and the selective filter By similarity
	Site	41	1	Seems to be involved in pH gating By similarity
Amino acid modifications
	Modified residue	64	1	Phosphoserine; by host By similarity
	Modified residue	82	1	Phosphoserine; by host By similarity
	Modified residue	93	1	Phosphoserine; by host By similarity
	Lipidation	50	1	S-palmitoyl cysteine; by host By similarity
	Glycosylation	20	1	N-linked (GlcNAc...); by host Potential
	Disulfide bond	17		Interchain (with C-17) By similarity
	Disulfide bond	19		Interchain (with C-19) By similarity
Natural variations
	Natural variant	10	1	P → H in strain: A/Puerto Rico/8/34/Mount Sinai/Wi-M2-P10H.
	Natural variant	10	1	P → L in strain: A/Puerto Rico/8/34/Mount Sinai/Wi-M2-P10L.
	Natural variant	27	1	A → T in strain: A/Puerto Rico/8/34/Mount Sinai/Wi, A/Puerto Rico/8/34/Mount Sinai/Wi-M2-P10L and A/Puerto Rico/8/34/Mount Sinai/Wi-M2-P10H.
	Natural variant	39	1	I → T in strain: A/Puerto Rico/8/34/Mount Sinai/Wi, A/Puerto Rico/8/34/Mount Sinai/Wi-M2-P10L and A/Puerto Rico/8/34/Mount Sinai/Wi-M2-P10H.
Experimental info
	Sequence conflict	27	1	A → I in ABD77677. Ref.5
	Sequence conflict	30	1	A → S in ABD77677. Ref.5
	Sequence conflict	54	1	R → L in ABD77677. Ref.5
	Sequence conflict	61	1	G → R in ABD77677. Ref.5
	Sequence conflict	77	1	R → Q in ABD77677. Ref.5

Sequences

	Sequence		Length	Mass (Da)
	Isoform M2 [UniParc]. Last modified November 1, 1988. Version 1. Checksum: 85858F6E84A97AB8	FASTA	97	11,045
	10 20 30 40 50 60 MSLLTEVETP IRNEWGCRCN GSSDPLAIAA NIIGILHLIL WILDRLFFKC IYRRFKYGLK 70 80 90 GGPSTEGVPK SMREEYRKEQ QSAVDADDGH FVSIELE
	Isoform M1 [UniParc]. See P03485.		–	–

References

[1]	"Cloning of influenza cDNA into M13: the sequence of the RNA segment encoding the A/PR/8/34 matrix protein." Winter G., Fields S. Nucleic Acids Res. 8:1965-1974(1980) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC RNA].
[2]	"Plasmid-only rescue of influenza A virus vaccine candidates." Schickli J.H., Flandorfer A., Nakaya T., Martinez-Sobrido L., Garcia-Sastre A., Palese P. Philos. Trans. R. Soc. Lond., B, Biol. Sci. 356:1965-1973(2001) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC RNA].
[3]	"Efficient generation and growth of influenza virus A/PR/8/34 from eight cDNA fragments." de Wit E., Spronken M.I.J., Bestebroer T.M., Rimmelzwaan G.F., Osterhaus A.D.M.E., Fouchier R.A.M. Virus Res. 103:155-161(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC RNA], REVERSE GENETICS.
[4]	"Influenza type a virus escape mutants emerge in vivo in the presence of antibodies to the ectodomain of matrix protein 2." Zharikova D., Mozdzanowska K., Feng J., Zhang M., Gerhard W. J. Virol. 79:6644-6654(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Strain: A/Puerto Rico/8/34/Mount Sinai/Wi, A/Puerto Rico/8/34/Mount Sinai/Wi-M2-P10H and A/Puerto Rico/8/34/Mount Sinai/Wi-M2-P10L.
[5]	"The NIAID influenza genome sequencing project." Ghedin E., Spiro D., Miller N., Zaborsky J., Feldblyum T., Subbu V., Shumway M., Sparenborg J., Groveman L., Halpin R., Sitz J., Koo H., Salzberg S.L., Webster R.G., Hoffmann E., Krauss S., Naeve C., Bao Y. , Bolotov P., Dernovoy D., Kiryutin B., Lipman D.J., Tatusova T. Submitted (MAR-2006) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC RNA].
[6]	"Assembly and budding of influenza virus." Nayak D.P., Hui E.K., Barman S. Virus Res. 106:147-165(2004) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
[7]	"Proton conduction through the M2 protein of the influenza A virus; a quantitative, mechanistic analysis of experimental data." Lear J.D. FEBS Lett. 552:17-22(2003) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
[8]	"Computational studies of proton transport through the M2 channel." Wu Y., Voth G.A. FEBS Lett. 552:23-27(2003) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.

Cross-references

Sequence databases
EMBL GenBank DDBJ	V01099 Genomic RNA. Translation: CAA24283.1. Sequence problems. AF389121 Genomic RNA. Translation: AAM75162.1. EF467824 Genomic RNA. Translation: ABO21713.1. AY768951 mRNA. Translation: AAV41244.1. AY768952 mRNA. Translation: AAV41245.1. AY768953 mRNA. Translation: AAV41246.1. CY009445 Genomic RNA. Translation: ABD77677.1.
RefSeq	NP_040979.2. NC_002016.1.
3D structure databases
ProteinModelPortal	P06821.
SMR	P06821. Positions 23-60.
ModBase	Search...
Protein-protein interaction databases
IntAct	P06821. 12 interactions.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
GeneID	956528.
Enzyme and pathway databases
Reactome	REACT_116125. Disease.
Family and domain databases
InterPro	IPR002089. Flu_M2. [Graphical view]
Pfam	PF00599. Flu_M2. 1 hit. [Graphical view]
ProDom	PD001031. Flu_M2. 1 hit. [Graphical view] [Entries sharing at least one domain]
ProtoNet	Search...
Other
ChEMBL	CHEMBL1932894.

Entry information

Entry name

M2_I34A1

Accession

Primary (citable) accession number: P06821
Secondary accession number(s): A4GXH7 , Q20N37, Q5UAV4, Q5UAV5, Q5UAV6, Q84105, Q8JUU3

Entry history

Integrated into UniProtKB/Swiss-Prot:	January 1, 1988
Last sequence update:	November 1, 1988
Last modified:	May 1, 2013
This is version 93 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Viral Protein Annotation Program