P13285 (LMP2_EBVB9) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Latent membrane protein 2

Alternative name(s):
Terminal protein

Gene names

Name:

LMP2

Organism

Epstein-Barr virus (strain B95-8) (HHV-4) (Human herpesvirus 4) [Reference proteome]

Taxonomic identifier

10377 [NCBI]

Taxonomic lineage

Viruses › dsDNA viruses, no RNA stage › Herpesvirales › Herpesviridae › Gammaherpesvirinae › Lymphocryptovirus › Epstein-Barr virus (strain GD1)

Virus host

Homo sapiens (Human) [TaxID: 9606]

Protein attributes

Sequence length	497 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Isoform LMP2A maintains EBV latent infection of B-lymphocyte, by preventing lytic reactivation of the virus in response to surface immunoglobulin (sIg) cross-linking. Acts like a dominant negative inhibitor of the sIg-associated protein tyrosine kinases, LYN and SYK. Also blocks translocation of the B-cell antigen receptor (BCR) into lipid rafts, preventing the subsequent signaling and accelerated internalization of the BCR upon BCR cross-linking. Serves as a molecular scaffold to recruit SYK, LYN and E3 protein-ubiquitin ligases, such as ITCH and NEDD4L, leading to ubiquitination and potential degradation of both tyrosines kinases. Possesses a constitutive signaling activity in non-transformed cells, inducing bypass of normal B lymphocyte developmental checkpoints allowing immunoglobulin-negative cells to colonize peripheral lymphoid organs. Ref.5 Ref.8 Isoform LMP2B may be a negative regulator of isoform LMP2A. Ref.5 Ref.8
Subunit structure	Isoform LMP2A cytoplasmic N-terminal domain interacts with human SRC family protein tyrosine kinases SYK and LYN. Binds human ITCH, WWP2 and NEDD4L. Ref.6 Ref.9
Subcellular location	Isoform LMP2A: Host cell membrane; Multi-pass membrane protein. Note: Isoform LMP2A is localized in plasma membrane lipid rafts. Ref.10 Ref.11 Isoform LMP2B: Host endomembrane system; Multi-pass membrane protein. Host cytoplasm › host perinuclear region. Note: Isoform LMP2B localizes to perinuclear regions. Ref.10 Ref.11
Post-translational modification	Isoform LMP2A is phosphorylated on cytoplasmic N-terminal tyrosines residues, possibly by human LYN. Ref.4 Can be ubiquitinated by human ITCH and WWP2 on the N-terminus in a lysine-independent manner.
Miscellaneous	In healthy individuals, EBV typically establishes a persistent latent infection in which the virus can be detected in resting, nonproliferating peripheral B-lymphocytes. These latently infected cells express only 2 virally encoded genes, LMP2A and EBNA1.
Sequence similarities	Belongs to the herpesviridae LMP-2 family.

Ontologies

Keywords
Biological process	Host-virus interaction Modulation of host E3 ubiquitin ligases by virus Modulation of host ubiquitin pathway by virus
Cellular component	Host cell membrane Host cytoplasm Host membrane Membrane
Coding sequence diversity	Alternative splicing
Domain	Transmembrane Transmembrane helix
PTM	Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	modulation by virus of host ubiquitin-protein ligase activity Inferred from electronic annotation. Source: UniProtKB-KW viral latency Inferred from electronic annotation. Source: InterPro
Cellular_component	host cell endomembrane system Inferred from electronic annotation. Source: UniProtKB-SubCell host cell perinuclear region of cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell host cell plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Alternative products

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

Isoform LMP2A (identifier: P13285-1)

Also known as: TP1;

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 LMP2B (identifier: P13285-2)

Also known as: TP2;

The sequence of this isoform differs from the canonical sequence as follows:
     1-119: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 497	497	Latent membrane protein 2		PRO_0000116280
Regions
	Topological domain	1 – 123	123	Cytoplasmic Potential
	Transmembrane	124 – 144	21	Helical; Potential
	Topological domain	145 – 147	3	Extracellular Potential
	Transmembrane	148 – 168	21	Helical; Potential
	Topological domain	169 – 177	9	Cytoplasmic Potential
	Transmembrane	178 – 198	21	Helical; Potential
	Topological domain	199 – 211	13	Extracellular Potential
	Transmembrane	212 – 232	21	Helical; Potential
	Topological domain	233 – 241	9	Cytoplasmic Potential
	Transmembrane	242 – 262	21	Helical; Potential
	Topological domain	263 – 267	5	Extracellular Potential
	Transmembrane	268 – 288	21	Helical; Potential
	Topological domain	289 – 296	8	Cytoplasmic Potential
	Transmembrane	297 – 317	21	Helical; Potential
	Topological domain	318	1	Extracellular Potential
	Transmembrane	319 – 339	21	Helical; Potential
	Topological domain	340 – 354	15	Cytoplasmic Potential
	Transmembrane	355 – 375	21	Helical; Potential
	Topological domain	376 – 388	13	Extracellular Potential
	Transmembrane	389 – 409	21	Helical; Potential
	Topological domain	410 – 422	13	Cytoplasmic Potential
	Transmembrane	423 – 443	21	Helical; Potential
	Topological domain	444 – 449	6	Extracellular Potential
	Transmembrane	450 – 470	21	Helical; Potential
	Topological domain	471 – 497	27	Cytoplasmic Potential
	Motif	97 – 101	5	PPPPY WW-binding
Amino acid modifications
	Modified residue	112	1	Phosphotyrosine; by host Potential
Natural variations
	Alternative sequence	1 – 119	119	Missing in isoform LMP2B.		VSP_016139
Experimental info
	Mutagenesis	74	1	Y → F: Loss of interaction with human SYK. Ref.7
	Mutagenesis	85	1	Y → F: Loss of interaction with human SYK. Ref.7
	Mutagenesis	112	1	Y → F: Complete loss of phosphorylation. Ref.7

Sequences

	Sequence		Length	Mass (Da)
	Isoform LMP2A (TP1) [UniParc]. Last modified January 1, 1990. Version 1. Checksum: F4DC9BB3C1FD83F1	FASTA	497	53,011
	10 20 30 40 50 60 MGSLEMVPMG AGPPSPGGDP DGYDGGNNSQ YPSASGSSGN TPTPPNDEER ESNEEPPPPY 70 80 90 100 110 120 EDPYWGNGDR HSDYQPLGTQ DQSLYLGLQH DGNDGLPPPP YSPRDDSSQH IYEEAGRGSM 130 140 150 160 170 180 NPVCLPVIVA PYLFWLAAIA ASCFTASVST VVTATGLALS LLLLAAVASS YAAAQRKLLT 190 200 210 220 230 240 PVTVLTAVVT FFAICLTWRI EDPPFNSLLF ALLAAAGGLQ GIYVLVMLVL LILAYRRRWR 250 260 270 280 290 300 RLTVCGGIMF LACVLVLIVD AVLQLSPLLG AVTVVSMTLL LLAFVLWLSS PGGLGTLGAA 310 320 330 340 350 360 LLTLAAALAL LASLILGTLN LTTMFLLMLL WTLVVLLICS SCSSCPLSKI LLARLFLYAL 370 380 390 400 410 420 ALLLLASALI AGGSILQTNF KSLSSTEFIP NLFCMLLLIV AGILFILAIL TEWGSGNRTY 430 440 450 460 470 480 GPVFMCLGGL LTMVAGAVWL TVMSNTLLSA WILTAGFLIF LIGFALFGVI RCCRYCCYYC 490 LTLESEERPP TPYRNTV
	Isoform LMP2B (TP2) [UniParc]. Checksum: 43526142FFAEE1DC	FASTA	378	40,383
	10 20 30 40 50 60 MNPVCLPVIV APYLFWLAAI AASCFTASVS TVVTATGLAL SLLLLAAVAS SYAAAQRKLL 70 80 90 100 110 120 TPVTVLTAVV TFFAICLTWR IEDPPFNSLL FALLAAAGGL QGIYVLVMLV LLILAYRRRW 130 140 150 160 170 180 RRLTVCGGIM FLACVLVLIV DAVLQLSPLL GAVTVVSMTL LLLAFVLWLS SPGGLGTLGA 190 200 210 220 230 240 ALLTLAAALA LLASLILGTL NLTTMFLLML LWTLVVLLIC SSCSSCPLSK ILLARLFLYA 250 260 270 280 290 300 LALLLLASAL IAGGSILQTN FKSLSSTEFI PNLFCMLLLI VAGILFILAI LTEWGSGNRT 310 320 330 340 350 360 YGPVFMCLGG LLTMVAGAVW LTVMSNTLLS AWILTAGFLI FLIGFALFGV IRCCRYCCYY 370 CLTLESEERP PTPYRNTV

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"A spliced Epstein-Barr virus gene expressed in immortalized lymphocytes is created by circularization of the linear viral genome." Laux G., Perricaudet M., Farrell P.J. EMBO J. 7:769-774(1988) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Two related Epstein-Barr virus membrane proteins are encoded by separate genes." Sample J., Liebowitz D., Kieff E. J. Virol. 63:933-937(1989) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS LMP2A AND LMP2B).
[3]	"DNA sequence and expression of the B95-8 Epstein-Barr virus genome." Baer R., Bankier A.T., Biggin M.D., Deininger P.L., Farrell P.J., Gibson T.J., Hatfull G., Hudson G.S., Satchwell S.C., Seguin C., Tuffnell P.S., Barrell B.G. Nature 310:207-211(1984) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA] (ISOFORM LMP2A).
[4]	"An Epstein-Barr virus protein associated with cell growth transformation interacts with a tyrosine kinase." Longnecker R., Druker B., Roberts T.M., Kieff E. J. Virol. 65:3681-3692(1991) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION.
[5]	"An integral membrane protein (LMP2) blocks reactivation of Epstein-Barr virus from latency following surface immunoglobulin crosslinking." Miller C.L., Lee J.H., Kieff E., Longnecker R. Proc. Natl. Acad. Sci. U.S.A. 91:772-776(1994) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[6]	"Integral membrane protein 2 of Epstein-Barr virus regulates reactivation from latency through dominant negative effects on protein-tyrosine kinases." Miller C.L., Burkhardt A.L., Lee J.H., Stealey B., Longnecker R., Bolen J.B., Kieff E. Immunity 2:155-166(1995) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH HUMAN SYK AND LYN.
[7]	"Tyrosine 112 of latent membrane protein 2A is essential for protein tyrosine kinase loading and regulation of Epstein-Barr virus latency." Fruehling S., Swart R., Dolwick K.M., Kremmer E., Longnecker R. J. Virol. 72:7796-7806(1998) [PubMed] [Europe PMC] [Abstract] Cited for: MUTAGENESIS OF TYR-74; TYR-85 AND TYR-112.
[8]	"Epstein-Barr virus LMP2A drives B cell development and survival in the absence of normal B cell receptor signals." Caldwell R.G., Wilson J.B., Anderson S.J., Longnecker R. Immunity 9:405-411(1998) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[9]	"Latent membrane protein 2A of Epstein-Barr virus binds WW domain E3 protein-ubiquitin ligases that ubiquitinate B-cell tyrosine kinases." Winberg G., Matskova L., Chen F., Plant P., Rotin D., Gish G., Ingham R., Ernberg I., Pawson T. Mol. Cell. Biol. 20:8526-8535(2000) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH HUMAN ITCH AND NEDD4L.
[10]	"Epstein-Barr virus coopts lipid rafts to block the signaling and antigen transport functions of the BCR." Dykstra M.L., Longnecker R., Pierce S.K. Immunity 14:57-67(2001) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION.
[11]	"Epstein-Barr virus latent membrane protein 2B (LMP2B) co-localizes with LMP2A in perinuclear regions in transiently transfected cells." Lynch D.T., Zimmerman J.S., Rowe D.T. J. Gen. Virol. 83:1025-1035(2002) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION.
[12]	"Lysine-independent ubiquitination of Epstein-Barr virus LMP2A." Ikeda M., Ikeda A., Longnecker R. Virology 300:153-159(2002) [PubMed] [Europe PMC] [Abstract] Cited for: UBIQUITINATION.
[13]	"Allele-dependent similarity between viral and self-peptide presentation by HLA-B27 subtypes." Fiorillo M.T., Ruckert C., Hulsmeyer M., Sorrentino R., Saenger W., Ziegler A., Uchanska-Ziegler B. J. Biol. Chem. 280:2962-2971(2005) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.55 ANGSTROMS) OF 236-244.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

M24212 mRNA. Translation: AAA45887.1.
Y00835 mRNA. Translation: CAA68762.1.
V01555 Genomic DNA. No translation available.
AJ507799 Genomic DNA. Translation: CAD53383.1. Sequence problems.
AJ507799 Genomic DNA. Translation: CAD53382.1. Sequence problems.

PIR

WMBELM. A30178.

RefSeq

YP_401631.1. NC_007605.1.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1UXS	X-ray	1.55	C	236-244	[»]
1UXW	X-ray	1.71	C	236-244	[»]
2JO9	NMR	-	B	54-62	[»]
3BVN	X-ray	2.55	C/F	236-244	[»]
3REW	X-ray	1.90	C/F	426-434	[»]

ModBase

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Protein-protein interaction databases

MINT

MINT-6768292.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

GeneID

3783751.

Phylogenomic databases

ProtClustDB

CLSP2512497.

Family and domain databases

InterPro

IPR010881. Herpes_LMP2.
[Graphical view]

Pfam

PF07415. Herpes_LMP2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

P13285.

Entry information

Entry name

LMP2_EBVB9

Accession

Primary (citable) accession number: P13285
Secondary accession number(s): Q777H4, Q8AZK9

Entry history

Integrated into UniProtKB/Swiss-Prot:	January 1, 1990
Last sequence update:	January 1, 1990
Last modified:	April 3, 2013
This is version 80 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Viral Protein Annotation Program