Latent membrane protein 2 - Epstein-Barr virus (strain B95-8) (HHV-4)

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Reviewed, UniProtKB/Swiss-Prot P13285 (LMP2_EBVB9)

Last modified June 16, 2009. Version 59. History...

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Alternative products · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents

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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) [Complete proteome]

Taxonomic identifier

10377 [NCBI]

Taxonomic lineage

Viruses › dsDNA viruses, no RNA stage › Herpesvirales › Herpesviridae › Gammaherpesvirinae › Lymphocryptovirus

Virus host

Homo sapiens (Human) [TaxID: 9606]

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Protein attributes

Sequence length	497 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

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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.
Post-translational modification	Isoform LMP2A is phosphorylated on cytoplasmic N-terminal tyrosines residues, possibly by human LYN. Ref.4 Can be ubiquitinated at 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.

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Ontologies

Keywords
Biological process	Host-virus interaction
Cellular component	Cell membrane Cytoplasm Membrane
Coding sequence diversity	Alternative splicing
Domain	Transmembrane
PTM	Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome
Gene Ontology (GO)
Biological process	interspecies interaction between organisms Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-KW host cell cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW plasma membrane Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

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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.
Note: Isoform LMP2A is localized in plasma membrane lipid rafts. Ref.10 Ref.11

Isoform LMP2B (identifier: P13285-2) Also known as: TP2; The sequence of this isoform differs from the canonical sequence as follows: 1-119: Missing.
Note: Isoform LMP2B localizes to perinuclear regions.

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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

Potential

Topological domain

145 – 147

Extracellular Potential

Transmembrane

148 – 168

Potential

Topological domain

169 – 177

Cytoplasmic Potential

Transmembrane

178 – 198

Potential

Topological domain

199 – 211

Extracellular Potential

Transmembrane

212 – 232

Potential

Topological domain

233 – 241

Cytoplasmic Potential

Transmembrane

242 – 262

Potential

Topological domain

263 – 267

Extracellular Potential

Transmembrane

268 – 288

Potential

Topological domain

289 – 296

Cytoplasmic Potential

Transmembrane

297 – 317

Potential

Topological domain

318

Extracellular Potential

Transmembrane

319 – 339

Potential

Topological domain

340 – 354

Cytoplasmic Potential

Transmembrane

355 – 375

Potential

Topological domain

376 – 388

Extracellular Potential

Transmembrane

389 – 409

Potential

Topological domain

410 – 422

Cytoplasmic Potential

Transmembrane

423 – 443

Potential

Topological domain

444 – 449

Extracellular Potential

Transmembrane

450 – 470

Potential

Topological domain

471 – 497

Cytoplasmic Potential

Motif

97 – 101

PPPPY WW-binding

Amino acid modifications

Modified residue

112

Phosphotyrosine; by host Potential

Natural variations

Alternative sequence

1 – 119

119

Missing in isoform LMP2B.

VSP_016139

Experimental info

Mutagenesis

Y → F: Loss of interaction with human SYK. Ref.7

Mutagenesis

Y → F: Loss of interaction with human SYK. Ref.7

Mutagenesis

112

Y → F: Complete loss of phosphorylation. Ref.7

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Sequences

Sequence		Length	Mass (Da)
Isoform LMP2A (TP1) [UniParc]. Last modified January 1, 1990. Version 1. Checksum: F4DC9BB3C1FD83F1 Show »	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 « Hide
Isoform LMP2B (TP2). Checksum: 43526142FFAEE1DC Show »	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 « Hide

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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: 2840285] [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: 2536113] [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: 6087149] [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: 1710288] [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: 8290598] [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: 7895172] [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: 9733815] [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: 9768760] [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: 11046148] [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: 11163230] [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: 11961256] [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: 12202215] [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: 15537660] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.55 ANGSTROMS) OF 236-244.
+	Additional computationally mapped references.

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Cross-references

Sequence databases

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.

3D structure databases

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	[»]

ModBase

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Family and domain databases

InterPro

IPR010881. Herpes_LMP2.
[Graphical view]

Pfam

PF07415. Herpes_LMP2. 1 hit.
[Graphical view]

ProtoNet

Search...

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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:	June 16, 2009
This is version 59 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

Virus (Virus annotation project)

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Relevant documents

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

SIMILARITY comments

Index of protein domains and families