LMP2_EBVB9
ID LMP2_EBVB9 Reviewed; 497 AA.
AC P13285; Q777H4; Q8AZK9;
DT 01-JAN-1990, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1990, sequence version 1.
DT 25-MAY-2022, entry version 123.
DE RecName: Full=Latent membrane protein 2;
DE AltName: Full=Terminal protein;
GN Name=LMP2;
OS Epstein-Barr virus (strain B95-8) (HHV-4) (Human herpesvirus 4).
OC Viruses; Duplodnaviria; Heunggongvirae; Peploviricota; Herviviricetes;
OC Herpesvirales; Herpesviridae; Gammaherpesvirinae; Lymphocryptovirus.
OX NCBI_TaxID=10377;
OH NCBI_TaxID=9606; Homo sapiens (Human).
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2840285; DOI=10.1002/j.1460-2075.1988.tb02874.x;
RA Laux G., Perricaudet M., Farrell P.J.;
RT "A spliced Epstein-Barr virus gene expressed in immortalized lymphocytes is
RT created by circularization of the linear viral genome.";
RL EMBO J. 7:769-774(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS LMP2A AND LMP2B).
RX PubMed=2536113; DOI=10.1128/jvi.63.2.933-937.1989;
RA Sample J., Liebowitz D., Kieff E.;
RT "Two related Epstein-Barr virus membrane proteins are encoded by separate
RT genes.";
RL J. Virol. 63:933-937(1989).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA] (ISOFORM LMP2A).
RX PubMed=6087149; DOI=10.1038/310207a0;
RA Baer R., Bankier A.T., Biggin M.D., Deininger P.L., Farrell P.J.,
RA Gibson T.J., Hatfull G., Hudson G.S., Satchwell S.C., Seguin C.,
RA Tuffnell P.S., Barrell B.G.;
RT "DNA sequence and expression of the B95-8 Epstein-Barr virus genome.";
RL Nature 310:207-211(1984).
RN [4]
RP PHOSPHORYLATION.
RX PubMed=1710288; DOI=10.1128/jvi.65.7.3681-3692.1991;
RA Longnecker R., Druker B., Roberts T.M., Kieff E.;
RT "An Epstein-Barr virus protein associated with cell growth transformation
RT interacts with a tyrosine kinase.";
RL J. Virol. 65:3681-3692(1991).
RN [5]
RP FUNCTION.
RX PubMed=8290598; DOI=10.1073/pnas.91.2.772;
RA Miller C.L., Lee J.H., Kieff E., Longnecker R.;
RT "An integral membrane protein (LMP2) blocks reactivation of Epstein-Barr
RT virus from latency following surface immunoglobulin crosslinking.";
RL Proc. Natl. Acad. Sci. U.S.A. 91:772-776(1994).
RN [6]
RP INTERACTION WITH HUMAN SYK AND LYN.
RX PubMed=7895172; DOI=10.1016/s1074-7613(95)80040-9;
RA Miller C.L., Burkhardt A.L., Lee J.H., Stealey B., Longnecker R.,
RA Bolen J.B., Kieff E.;
RT "Integral membrane protein 2 of Epstein-Barr virus regulates reactivation
RT from latency through dominant negative effects on protein-tyrosine
RT kinases.";
RL Immunity 2:155-166(1995).
RN [7]
RP MUTAGENESIS OF TYR-74; TYR-85 AND TYR-112.
RX PubMed=9733815; DOI=10.1128/jvi.72.10.7796-7806.1998;
RA Fruehling S., Swart R., Dolwick K.M., Kremmer E., Longnecker R.;
RT "Tyrosine 112 of latent membrane protein 2A is essential for protein
RT tyrosine kinase loading and regulation of Epstein-Barr virus latency.";
RL J. Virol. 72:7796-7806(1998).
RN [8]
RP FUNCTION.
RX PubMed=9768760; DOI=10.1016/s1074-7613(00)80623-8;
RA Caldwell R.G., Wilson J.B., Anderson S.J., Longnecker R.;
RT "Epstein-Barr virus LMP2A drives B cell development and survival in the
RT absence of normal B cell receptor signals.";
RL Immunity 9:405-411(1998).
RN [9]
RP INTERACTION WITH HUMAN ITCH AND NEDD4L.
RX PubMed=11046148; DOI=10.1128/mcb.20.22.8526-8535.2000;
RA Winberg G., Matskova L., Chen F., Plant P., Rotin D., Gish G., Ingham R.,
RA Ernberg I., Pawson T.;
RT "Latent membrane protein 2A of Epstein-Barr virus binds WW domain E3
RT protein-ubiquitin ligases that ubiquitinate B-cell tyrosine kinases.";
RL Mol. Cell. Biol. 20:8526-8535(2000).
RN [10]
RP SUBCELLULAR LOCATION.
RX PubMed=11163230; DOI=10.1016/s1074-7613(01)00089-9;
RA Dykstra M.L., Longnecker R., Pierce S.K.;
RT "Epstein-Barr virus coopts lipid rafts to block the signaling and antigen
RT transport functions of the BCR.";
RL Immunity 14:57-67(2001).
RN [11]
RP SUBCELLULAR LOCATION.
RX PubMed=11961256; DOI=10.1099/0022-1317-83-5-1025;
RA Lynch D.T., Zimmerman J.S., Rowe D.T.;
RT "Epstein-Barr virus latent membrane protein 2B (LMP2B) co-localizes with
RT LMP2A in perinuclear regions in transiently transfected cells.";
RL J. Gen. Virol. 83:1025-1035(2002).
RN [12]
RP UBIQUITINATION.
RX PubMed=12202215; DOI=10.1006/viro.2002.1562;
RA Ikeda M., Ikeda A., Longnecker R.;
RT "Lysine-independent ubiquitination of Epstein-Barr virus LMP2A.";
RL Virology 300:153-159(2002).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (1.55 ANGSTROMS) OF 236-244.
RX PubMed=15537660; DOI=10.1074/jbc.m410807200;
RA Fiorillo M.T., Ruckert C., Hulsmeyer M., Sorrentino R., Saenger W.,
RA Ziegler A., Uchanska-Ziegler B.;
RT "Allele-dependent similarity between viral and self-peptide presentation by
RT HLA-B27 subtypes.";
RL J. Biol. Chem. 280:2962-2971(2005).
CC -!- FUNCTION: Isoform LMP2A maintains EBV latent infection of B-lymphocyte,
CC by preventing lytic reactivation of the virus in response to surface
CC immunoglobulin (sIg) cross-linking. Acts like a dominant negative
CC inhibitor of the sIg-associated protein tyrosine kinases, LYN and SYK.
CC Also blocks translocation of the B-cell antigen receptor (BCR) into
CC lipid rafts, preventing the subsequent signaling and accelerated
CC internalization of the BCR upon BCR cross-linking. Serves as a
CC molecular scaffold to recruit SYK, LYN and E3 protein-ubiquitin
CC ligases, such as ITCH and NEDD4L, leading to ubiquitination and
CC potential degradation of both tyrosines kinases. Possesses a
CC constitutive signaling activity in non-transformed cells, inducing
CC bypass of normal B lymphocyte developmental checkpoints allowing
CC immunoglobulin-negative cells to colonize peripheral lymphoid organs.
CC -!- FUNCTION: Isoform LMP2B may be a negative regulator of isoform LMP2A.
CC -!- SUBUNIT: Isoform LMP2A cytoplasmic N-terminal domain interacts with
CC human SRC family protein tyrosine kinases SYK and LYN. Binds human
CC ITCH, WWP2 and NEDD4L. {ECO:0000269|PubMed:11046148,
CC ECO:0000269|PubMed:7895172}.
CC -!- INTERACTION:
CC P13285; Q96J02: ITCH; Xeno; NbExp=3; IntAct=EBI-7181113, EBI-1564678;
CC -!- SUBCELLULAR LOCATION: [Isoform LMP2A]: Host cell membrane
CC {ECO:0000269|PubMed:11163230, ECO:0000269|PubMed:11961256}; Multi-pass
CC membrane protein {ECO:0000269|PubMed:11163230,
CC ECO:0000269|PubMed:11961256}. Note=Isoform LMP2A is localized in plasma
CC membrane lipid rafts. {ECO:0000269|PubMed:11163230}.
CC -!- SUBCELLULAR LOCATION: [Isoform LMP2B]: Host endomembrane system
CC {ECO:0000269|PubMed:11961256}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:11961256}. Host cytoplasm, host perinuclear region
CC {ECO:0000269|PubMed:11961256}. Note=Isoform LMP2B localizes to
CC perinuclear regions. {ECO:0000269|PubMed:11961256}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=LMP2A; Synonyms=TP1;
CC IsoId=P13285-1; Sequence=Displayed;
CC Name=LMP2B; Synonyms=TP2;
CC IsoId=P13285-2; Sequence=VSP_016139;
CC -!- PTM: Isoform LMP2A is phosphorylated on cytoplasmic N-terminal tyrosine
CC residues, possibly by human LYN. {ECO:0000269|PubMed:1710288}.
CC -!- PTM: Can be ubiquitinated by human ITCH and WWP2 on the N-terminus in a
CC lysine-independent manner. {ECO:0000269|PubMed:12202215}.
CC -!- MISCELLANEOUS: In healthy individuals, EBV typically establishes a
CC persistent latent infection in which the virus can be detected in
CC resting, nonproliferating peripheral B-lymphocytes. These latently
CC infected cells express only 2 virally encoded genes, LMP2A and EBNA1.
CC -!- SIMILARITY: Belongs to the herpesviridae LMP-2 family. {ECO:0000305}.
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DR EMBL; M24212; AAA45887.1; -; mRNA.
DR EMBL; Y00835; CAA68762.1; -; mRNA.
DR EMBL; V01555; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AJ507799; CAD53383.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AJ507799; CAD53382.1; ALT_SEQ; Genomic_DNA.
DR PIR; A30178; WMBELM.
DR RefSeq; YP_401631.1; NC_007605.1.
DR RefSeq; YP_401632.1; NC_007605.1.
DR PDB; 1UXS; X-ray; 1.55 A; C=236-244.
DR PDB; 1UXW; X-ray; 1.71 A; C=236-244.
DR PDB; 2JO9; NMR; -; B=54-62.
DR PDB; 3BVN; X-ray; 2.55 A; C/F=236-244.
DR PDB; 3REW; X-ray; 1.90 A; C/F=426-434.
DR PDB; 5GRD; X-ray; 1.80 A; C=340-349.
DR PDB; 5GSD; X-ray; 2.30 A; C=343-349.
DR PDBsum; 1UXS; -.
DR PDBsum; 1UXW; -.
DR PDBsum; 2JO9; -.
DR PDBsum; 3BVN; -.
DR PDBsum; 3REW; -.
DR PDBsum; 5GRD; -.
DR PDBsum; 5GSD; -.
DR BMRB; P13285; -.
DR SMR; P13285; -.
DR BioGRID; 3509104; 3.
DR ELM; P13285; -.
DR IntAct; P13285; 82.
DR MINT; P13285; -.
DR TCDB; 9.B.387.2.1; the viral latent membrane protein (vlmp) family.
DR SwissPalm; P13285; -.
DR PRIDE; P13285; -.
DR DNASU; 3783751; -.
DR DNASU; 3783760; -.
DR GeneID; 3783751; -.
DR GeneID; 3783760; -.
DR KEGG; vg:3783751; -.
DR KEGG; vg:3783760; -.
DR SIGNOR; P13285; -.
DR EvolutionaryTrace; P13285; -.
DR Proteomes; UP000153037; Genome.
DR GO; GO:0033645; C:host cell endomembrane system; IEA:UniProtKB-SubCell.
DR GO; GO:0044220; C:host cell perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0020002; C:host cell plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0039648; P:modulation by virus of host protein ubiquitination; IEA:UniProtKB-KW.
DR GO; GO:0039649; P:modulation by virus of host ubiquitin-protein ligase activity; IEA:UniProtKB-KW.
DR GO; GO:0019042; P:viral latency; IEA:InterPro.
DR InterPro; IPR010881; Herpes_LMP2.
DR Pfam; PF07415; Herpes_LMP2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Host cell membrane; Host cytoplasm;
KW Host membrane; Host-virus interaction; Membrane;
KW Modulation of host E3 ubiquitin ligases by virus;
KW Modulation of host ubiquitin pathway by virus; Phosphoprotein;
KW Reference proteome; Transmembrane; Transmembrane helix; Ubl conjugation.
FT CHAIN 1..497
FT /note="Latent membrane protein 2"
FT /id="PRO_0000116280"
FT TOPO_DOM 1..123
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 124..144
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 145..147
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 148..168
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 169..177
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 178..198
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 199..211
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 212..232
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 233..241
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 242..262
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 263..267
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 268..288
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 289..296
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 297..317
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 318
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 319..339
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 340..354
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 355..375
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 376..388
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 389..409
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 410..422
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 423..443
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 444..449
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 450..470
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 471..497
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 1..108
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 97..101
FT /note="PPxY motif"
FT COMPBIAS 26..46
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 73..87
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 112
FT /note="Phosphotyrosine; by host"
FT /evidence="ECO:0000255"
FT VAR_SEQ 1..119
FT /note="Missing (in isoform LMP2B)"
FT /evidence="ECO:0000303|PubMed:2536113"
FT /id="VSP_016139"
FT MUTAGEN 74
FT /note="Y->F: Loss of interaction with human SYK."
FT /evidence="ECO:0000269|PubMed:9733815"
FT MUTAGEN 85
FT /note="Y->F: Loss of interaction with human SYK."
FT /evidence="ECO:0000269|PubMed:9733815"
FT MUTAGEN 112
FT /note="Y->F: Complete loss of phosphorylation."
FT /evidence="ECO:0000269|PubMed:9733815"
SQ SEQUENCE 497 AA; 53011 MW; F4DC9BB3C1FD83F1 CRC64;
MGSLEMVPMG AGPPSPGGDP DGYDGGNNSQ YPSASGSSGN TPTPPNDEER ESNEEPPPPY
EDPYWGNGDR HSDYQPLGTQ DQSLYLGLQH DGNDGLPPPP YSPRDDSSQH IYEEAGRGSM
NPVCLPVIVA PYLFWLAAIA ASCFTASVST VVTATGLALS LLLLAAVASS YAAAQRKLLT
PVTVLTAVVT FFAICLTWRI EDPPFNSLLF ALLAAAGGLQ GIYVLVMLVL LILAYRRRWR
RLTVCGGIMF LACVLVLIVD AVLQLSPLLG AVTVVSMTLL LLAFVLWLSS PGGLGTLGAA
LLTLAAALAL LASLILGTLN LTTMFLLMLL WTLVVLLICS SCSSCPLSKI LLARLFLYAL
ALLLLASALI AGGSILQTNF KSLSSTEFIP NLFCMLLLIV AGILFILAIL TEWGSGNRTY
GPVFMCLGGL LTMVAGAVWL TVMSNTLLSA WILTAGFLIF LIGFALFGVI RCCRYCCYYC
LTLESEERPP TPYRNTV
