M2_I72A8
ID M2_I72A8 Reviewed; 97 AA.
AC P0DOF8; P03490; P63231; Q1K9D8;
DT 10-MAY-2017, integrated into UniProtKB/Swiss-Prot.
DT 10-MAY-2017, sequence version 1.
DT 02-JUN-2021, entry version 33.
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/Udorn/1972 H3N2).
OC Viruses; Riboviria; Orthornavirae; Negarnaviricota; Polyploviricotina;
OC Insthoviricetes; Articulavirales; Orthomyxoviridae; Alphainfluenzavirus.
OX NCBI_TaxID=385599;
OH NCBI_TaxID=8782; Aves.
OH NCBI_TaxID=9721; Cetacea (whales).
OH NCBI_TaxID=9606; Homo sapiens (Human).
OH NCBI_TaxID=9709; Phocidae (true seals).
OH NCBI_TaxID=9823; Sus scrofa (Pig).
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RX PubMed=6945577; DOI=10.1073/pnas.78.7.4170;
RA Lamb R.A., Lai C.-J., Choppin P.W.;
RT "Sequences of mRNAs derived from genome RNA segment 7 of influenza virus:
RT colinear and interrupted mRNAs code for overlapping proteins.";
RL Proc. Natl. Acad. Sci. U.S.A. 78:4170-4174(1981).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RX PubMed=7257189; DOI=10.1016/0042-6822(81)90319-6;
RA Lamb R.A., Lai C.-J.;
RT "Conservation of the influenza virus membrane protein (M1) amino acid
RT sequence and an open reading frame of RNA segment 7 encoding a second
RT protein (M2) in H1N1 and H3N2 strains.";
RL Virology 112:746-751(1981).
RN [3]
RP DISULFIDE BONDS, AND SUBUNIT.
RX PubMed=2053285; DOI=10.1016/0042-6822(91)90115-r;
RA Holsinger L.J., Lamb R.A.;
RT "Influenza virus M2 integral membrane protein is a homotetramer stabilized
RT by formation of disulfide bonds.";
RL Virology 183:32-43(1991).
RN [4]
RP FUNCTION, AND MUTAGENESIS OF VAL-27; ALA-30; SER-31; GLY-34 AND TRP-41.
RX PubMed=7508997; DOI=10.1128/jvi.68.3.1551-1563.1994;
RA Holsinger L.J., Nichani D., Pinto L.H., Lamb R.A.;
RT "Influenza A virus M2 ion channel protein: a structure-function analysis.";
RL J. Virol. 68:1551-1563(1994).
RN [5]
RP PHOSPHORYLATION AT SER-64; SER-82; SER-89 AND SER-93, AND MUTAGENESIS OF
RP SER-64.
RX PubMed=7529332; DOI=10.1128/jvi.69.2.1219-1225.1995;
RA Holsinger L.J., Shaughnessy M.A., Micko A., Pinto L.H., Lamb R.A.;
RT "Analysis of the posttranslational modifications of the influenza virus M2
RT protein.";
RL J. Virol. 69:1219-1225(1995).
RN [6]
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 [7]
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 [8]
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 [9]
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 (By similarity). {ECO:0000250,
CC ECO:0000269|PubMed:7508997}.
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 (PubMed:2053285). May interact
CC with matrix protein 1 (PubMed:16873274). {ECO:0000255|HAMAP-
CC Rule:MF_04069, ECO:0000269|PubMed:16873274,
CC ECO:0000269|PubMed:2053285}.
CC -!- SUBCELLULAR LOCATION: Virion membrane {ECO:0000255|HAMAP-
CC Rule:MF_04069}. Host apical cell membrane {ECO:0000255|HAMAP-
CC Rule:MF_04069}; Single-pass type III membrane protein
CC {ECO:0000255|HAMAP-Rule:MF_04069}. Note=Abundantly expressed at the
CC apical 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=P0DOF8-1, P03490-1, P63231-1;
CC Sequence=Displayed;
CC Name=M1;
CC IsoId=P0DOF7-1, P03486-1, P63233-1;
CC Sequence=External;
CC -!- DOMAIN: Cytoplasmic tail plays an important role in virion assembly and
CC morphogenesis. {ECO:0000255|HAMAP-Rule:MF_04069}.
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; J02167; AAA43303.1; -; Genomic_RNA.
DR SMR; P0DOF8; -.
DR ChEMBL; CHEMBL2052; -.
DR iPTMnet; P0DOF8; -.
DR Proteomes; UP000171580; 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:0044385; C:integral to membrane of host cell; IEA:UniProtKB-UniRule.
DR GO; GO:0055036; C:virion membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005216; F:ion channel activity; IEA:UniProtKB-UniRule.
DR GO; GO:0015078; F:proton transmembrane transporter activity; IEA:UniProtKB-UniRule.
DR GO; GO:0039707; P:pore formation by virus in membrane of host cell; 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 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; Signal-anchor;
KW Transmembrane; Transmembrane helix; Transport; Viral ion channel; Virion.
FT CHAIN 1..97
FT /note="Matrix protein 2"
FT /id="PRO_0000078892"
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..88
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 67..88
FT /note="Basic and acidic residues"
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 SITE 71
FT /note="Not phosphorylated"
FT MOD_RES 64
FT /note="Phosphoserine; by host"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04069,
FT ECO:0000269|PubMed:7529332"
FT MOD_RES 82
FT /note="Phosphoserine; by host"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04069,
FT ECO:0000269|PubMed:7529332"
FT MOD_RES 89
FT /note="Phosphoserine; by host"
FT /evidence="ECO:0000269|PubMed:7529332"
FT MOD_RES 93
FT /note="Phosphoserine; by host"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04069,
FT ECO:0000269|PubMed:7529332"
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 ECO:0000269|PubMed:2053285"
FT DISULFID 19
FT /note="Interchain (with C-19)"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04069,
FT ECO:0000269|PubMed:2053285"
FT MUTAGEN 27
FT /note="V->A: Increased channel activity. Resistant to
FT amantatine."
FT /evidence="ECO:0000269|PubMed:7508997"
FT MUTAGEN 27
FT /note="V->S: Increased channel activity. Resistant to
FT amantatine."
FT /evidence="ECO:0000269|PubMed:7508997"
FT MUTAGEN 27
FT /note="V->T: Increased channel activity."
FT /evidence="ECO:0000269|PubMed:7508997"
FT MUTAGEN 30
FT /note="A->P: Almost complete loss of channel activity.
FT Resistant to amantatine."
FT /evidence="ECO:0000269|PubMed:7508997"
FT MUTAGEN 30
FT /note="A->T: Greatly reduced channel activity. Resistant to
FT amantatine."
FT /evidence="ECO:0000269|PubMed:7508997"
FT MUTAGEN 31
FT /note="S->N: No effect on channel activity. Resistant to
FT amantatine."
FT /evidence="ECO:0000269|PubMed:7508997"
FT MUTAGEN 34
FT /note="G->E: Increased channel activity. Resistant to
FT amantatine."
FT /evidence="ECO:0000269|PubMed:7508997"
FT MUTAGEN 41
FT /note="W->A: Almost complete loss of channel activity."
FT /evidence="ECO:0000269|PubMed:7508997"
FT MUTAGEN 64
FT /note="S->A: 85% reduction in phosphate labeling of M2
FT protein."
FT /evidence="ECO:0000269|PubMed:7529332"
SQ SEQUENCE 97 AA; 11186 MW; 3CDD4DE90D7B16A4 CRC64;
MSLLTEVETP IRNEWGCRCN DSSDPLVVAA SIIGILHLIL WILDRLFFKC IYRFFEHGLK
RGPSTEGVPE SMREEYRKEQ QSAVDADDSH FVSIELE
