ID   M2_I33A0                Reviewed;          97 AA.
AC   P05780; Q67182;
DT   01-NOV-1988, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1988, sequence version 1.
DT   24-JAN-2024, entry version 129.
DE   RecName: Full=Matrix protein 2 {ECO:0000255|HAMAP-Rule:MF_04069};
DE   AltName: Full=Proton channel protein M2 {ECO:0000255|HAMAP-Rule:MF_04069};
GN   Name=M {ECO:0000255|HAMAP-Rule:MF_04069};
OS   Influenza A virus (strain A/Wilson-Smith/1933 H1N1) (Influenza A virus
OS   (strain A/WS/1933 H1N1)).
OC   Viruses; Riboviria; Orthornavirae; Negarnaviricota; Polyploviricotina;
OC   Insthoviricetes; Articulavirales; Orthomyxoviridae; Alphainfluenzavirus;
OC   Alphainfluenzavirus influenzae; Influenza A virus.
OX   NCBI_TaxID=381518;
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].
RC   STRAIN=A/WS/33, and A/WSN/33;
RX   PubMed=2701939; DOI=10.1093/nar/17.7.2870;
RA   Zebedee S.L., Lamb R.A.;
RT   "Nucleotide sequences of influenza A virus RNA segment 7: a comparison of
RT   five isolates.";
RL   Nucleic Acids Res. 17:2870-2870(1989).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RC   STRAIN=A/WSN/33;
RX   PubMed=3414185; DOI=10.1016/0168-1702(88)90021-4;
RA   Markushin S., Ghiasi H., Sokolov N., Shilov A., Sinitsin B., Brown D.,
RA   Klimov A., Nayak D.;
RT   "Nucleotide sequence of RNA segment 7 and the predicted amino sequence of
RT   M1 and M2 proteins of FPV/Weybridge (H7N7) and WSN (H1N1) influenza
RT   viruses.";
RL   Virus Res. 10:263-272(1988).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [GENOMIC RNA / MRNA].
RC   STRAIN=A/NWS/33, and A/WSN/33;
RX   PubMed=7710364; DOI=10.1007/bf01309872;
RA   Ward A.C.;
RT   "Specific changes in the M1 protein during adaptation of influenza virus to
RT   mouse.";
RL   Arch. Virol. 140:383-389(1995).
RN   [4]
RP   TOPOLOGY.
RX   PubMed=3882238; DOI=10.1016/0092-8674(85)90211-9;
RA   Lamb R.A., Zebedee S.L., Richardson C.D.;
RT   "Influenza virus M2 protein is an integral membrane protein expressed on
RT   the infected-cell surface.";
RL   Cell 40:627-633(1985).
RN   [5]
RP   SUBCELLULAR LOCATION.
RC   STRAIN=A/WSN/33;
RX   PubMed=1501289; DOI=10.1128/jvi.66.9.5542-5552.1992;
RA   Hughey P.G., Compans R.W., Zebedee S.L., Lamb R.A.;
RT   "Expression of the influenza A virus M2 protein is restricted to apical
RT   surfaces of polarized epithelial cells.";
RL   J. Virol. 66:5542-5552(1992).
RN   [6]
RP   DOMAIN, AND MUTAGENESIS OF 74-GLU--LYS-76 AND 77-ARG--GLU-79.
RX   PubMed=16699003; DOI=10.1128/jvi.00049-06;
RA   Iwatsuki-Horimoto K., Horimoto T., Noda T., Kiso M., Maeda J., Watanabe S.,
RA   Muramoto Y., Fujii K., Kawaoka Y.;
RT   "The cytoplasmic tail of the influenza A virus M2 protein plays a role in
RT   viral assembly.";
RL   J. Virol. 80:5233-5240(2006).
RN   [7]
RP   INTERACTION WITH MATRIX PROTEIN 1.
RX   PubMed=16873274; DOI=10.1128/jvi.00627-06;
RA   McCown M.F., Pekosz A.;
RT   "Distinct domains of the influenza a virus M2 protein cytoplasmic tail
RT   mediate binding to the M1 protein and facilitate infectious virus
RT   production.";
RL   J. Virol. 80:8178-8189(2006).
RN   [8]
RP   REVIEW.
RX   PubMed=12972146; DOI=10.1016/s0014-5793(03)00778-6;
RA   Lear J.D.;
RT   "Proton conduction through the M2 protein of the influenza A virus; a
RT   quantitative, mechanistic analysis of experimental data.";
RL   FEBS Lett. 552:17-22(2003).
RN   [9]
RP   REVIEW.
RX   PubMed=12972147; DOI=10.1016/s0014-5793(03)00779-8;
RA   Wu Y., Voth G.A.;
RT   "Computational studies of proton transport through the M2 channel.";
RL   FEBS Lett. 552:23-27(2003).
RN   [10]
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).
CC   -!- FUNCTION: Forms a proton-selective ion channel that is necessary for
CC       the efficient release of the viral genome during virus entry. After
CC       attaching to the cell surface, the virion enters the cell by
CC       endocytosis. Acidification of the endosome triggers M2 ion channel
CC       activity. The influx of protons into virion interior is believed to
CC       disrupt interactions between the viral ribonucleoprotein (RNP), matrix
CC       protein 1 (M1), and lipid bilayers, thereby freeing the viral genome
CC       from interaction with viral proteins and enabling RNA segments to
CC       migrate to the host cell nucleus, where influenza virus RNA
CC       transcription and replication occur. Also plays a role in viral
CC       proteins secretory pathway. Elevates the intravesicular pH of normally
CC       acidic compartments, such as trans-Golgi network, preventing newly
CC       formed hemagglutinin from premature switching to the fusion-active
CC       conformation. {ECO:0000255|HAMAP-Rule:MF_04069}.
CC   -!- ACTIVITY REGULATION: The M2 protein from most influenza A strains is
CC       inhibited by amantadine and rimantadine, resulting in viral uncoating
CC       incapacity. Emergence of amantadine-resistant variants is usually
CC       rapid.
CC   -!- SUBUNIT: Homotetramer; composed of two disulfide-linked dimers held
CC       together by non-covalent interactions. May interact with matrix protein
CC       1. {ECO:0000255|HAMAP-Rule:MF_04069}.
CC   -!- SUBCELLULAR LOCATION: Virion membrane {ECO:0000255|HAMAP-Rule:MF_04069,
CC       ECO:0000269|PubMed:1501289}. Host apical cell membrane
CC       {ECO:0000255|HAMAP-Rule:MF_04069, ECO:0000269|PubMed:1501289}; Single-
CC       pass type III membrane protein {ECO:0000255|HAMAP-Rule:MF_04069,
CC       ECO:0000269|PubMed:1501289}. Note=Abundantly expressed at the apical
CC       plasma membrane in infected polarized epithelial cells, in close
CC       proximity to budding and assembled virions. Minor component of virions
CC       (only 16-20 molecules/virion). {ECO:0000255|HAMAP-Rule:MF_04069}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC         Comment=Only the first 9 residues are shared by the 2 isoforms.;
CC       Name=M2;
CC         IsoId=P05780-1; Sequence=Displayed;
CC       Name=M1;
CC         IsoId=P05777-1; Sequence=External;
CC   -!- DOMAIN: Cytoplasmic tail plays an important role in virion assembly and
CC       morphogenesis. {ECO:0000255|HAMAP-Rule:MF_04069,
CC       ECO:0000269|PubMed:16699003}.
CC   -!- MISCELLANEOUS: When the channel is activated, one or more imidazole
CC       moieties of His-37 probably become bi-protonated. {ECO:0000255|HAMAP-
CC       Rule:MF_04069}.
CC   -!- SIMILARITY: Belongs to the influenza viruses matrix protein M2 family.
CC       {ECO:0000255|HAMAP-Rule:MF_04069}.
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DR   EMBL; X08088; CAA30883.1; -; Genomic_RNA.
DR   EMBL; X08089; CAA30885.1; -; Genomic_RNA.
DR   EMBL; M23922; AAA43274.1; -; Genomic_RNA.
DR   EMBL; L25814; AAA91322.1; -; mRNA.
DR   EMBL; L25818; AAA91324.1; -; Genomic_RNA.
DR   SMR; P05780; -.
DR   IntAct; P05780; 1.
DR   GlyCosmos; P05780; 1 site, No reported glycans.
DR   Proteomes; UP000000834; 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:0005216; F:monoatomic ion channel activity; IEA:UniProtKB-UniRule.
DR   GO; GO:0015078; F:proton transmembrane transporter activity; IEA:UniProtKB-UniRule.
DR   GO; GO:0051259; P:protein complex oligomerization; IEA:UniProtKB-UniRule.
DR   GO; GO:0039521; P:suppression by virus of host autophagy; IEA:UniProtKB-UniRule.
DR   GO; GO:0039707; P:virus-mediated pore formation in host cell membrane; IEA:UniProtKB-UniRule.
DR   Gene3D; 6.10.250.1640; -; 1.
DR   HAMAP; MF_04069; INFV_M2; 1.
DR   InterPro; IPR002089; Flu_M2.
DR   Pfam; PF00599; Flu_M2; 1.
PE   1: Evidence at protein level;
KW   Alternative splicing; Disulfide bond; Glycoprotein; Host cell membrane;
KW   Host membrane; Host-virus interaction; Hydrogen ion transport;
KW   Inhibition of host autophagy by virus; Ion channel; Ion transport;
KW   Lipoprotein; Membrane; Palmitate; Phosphoprotein; Reference proteome;
KW   Signal-anchor; Transmembrane; Transmembrane helix; Transport;
KW   Viral ion channel; Virion.
FT   CHAIN           1..97
FT                   /note="Matrix protein 2"
FT                   /id="PRO_0000078894"
FT   TOPO_DOM        1..22
FT                   /note="Virion surface"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04069"
FT   TRANSMEM        23..43
FT                   /note="Helical; Signal-anchor for type III membrane
FT                   protein"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04069"
FT   TOPO_DOM        44..97
FT                   /note="Intravirion"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04069"
FT   REGION          60..80
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   SITE            37
FT                   /note="Essential for channel activity, possibly by being
FT                   protonated during channel activation, and by forming the
FT                   channel gate and the selective filter"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04069"
FT   SITE            41
FT                   /note="Seems to be involved in pH gating"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04069"
FT   MOD_RES         64
FT                   /note="Phosphoserine; by host"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04069"
FT   LIPID           50
FT                   /note="S-palmitoyl cysteine; by host"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04069"
FT   CARBOHYD        20
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04069"
FT   DISULFID        17
FT                   /note="Interchain (with C-17)"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04069"
FT   DISULFID        19
FT                   /note="Interchain (with C-19)"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04069"
FT   MUTAGEN         74..76
FT                   /note="EEY->AAA: Loss of infectivity, and modification of
FT                   virion morphology."
FT                   /evidence="ECO:0000269|PubMed:16699003"
FT   MUTAGEN         77..79
FT                   /note="RKE->AAA: Loss of infectivity, and modification of
FT                   virion morphology."
FT                   /evidence="ECO:0000269|PubMed:16699003"
FT   CONFLICT        34
FT                   /note="G -> E (in Ref. 3; AAA91324)"
FT   CONFLICT        55
FT                   /note="F -> L (in Ref. 2; AAA43274)"
SQ   SEQUENCE   97 AA;  11313 MW;  1B5A86F9E0CD71DE CRC64;
     MSLLTEVETP IRNEWGCRCN DSSDPLVIAA NIIGILHLIL WILDRLFFKC IYRRFKYGLK
     RGPSTEGVPE SMREEYRKEQ QNAVDVDDGH FVNIELE
//