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P13285

- LMP2_EBVB9

UniProt

P13285 - LMP2_EBVB9

Protein

Latent membrane protein 2

Gene

LMP2

Organism
Epstein-Barr virus (strain B95-8) (HHV-4) (Human herpesvirus 4)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 86 (01 Oct 2014)
      Sequence version 1 (01 Jan 1990)
      Previous versions | rss
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    Functioni

    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.
    Isoform LMP2B may be a negative regulator of isoform LMP2A.

    GO - Molecular functioni

    1. protein binding Source: IntAct

    GO - Biological processi

    1. modulation by virus of host ubiquitin-protein ligase activity Source: UniProtKB-KW
    2. viral latency Source: InterPro

    Keywords - Biological processi

    Host-virus interaction, Modulation of host E3 ubiquitin ligases by virus, Modulation of host ubiquitin pathway by virus

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Latent membrane protein 2
    Alternative name(s):
    Terminal protein
    Gene namesi
    Name:LMP2
    OrganismiEpstein-Barr virus (strain B95-8) (HHV-4) (Human herpesvirus 4)
    Taxonomic identifieri10377 [NCBI]
    Taxonomic lineageiVirusesdsDNA viruses, no RNA stageHerpesviralesHerpesviridaeGammaherpesvirinaeLymphocryptovirus
    Virus hostiHomo sapiens (Human) [TaxID: 9606]
    ProteomesiUP000007640: Genome

    Subcellular locationi

    Isoform LMP2A : Host cell membrane; Multi-pass membrane protein
    Note: Isoform LMP2A is localized in plasma membrane lipid rafts.

    GO - Cellular componenti

    1. host cell endomembrane system Source: UniProtKB-SubCell
    2. host cell perinuclear region of cytoplasm Source: UniProtKB-SubCell
    3. host cell plasma membrane Source: UniProtKB-SubCell
    4. integral component of membrane Source: UniProtKB-KW

    Keywords - Cellular componenti

    Host cell membrane, Host cytoplasm, Host membrane, Membrane

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi74 – 741Y → F: Loss of interaction with human SYK. 1 Publication
    Mutagenesisi85 – 851Y → F: Loss of interaction with human SYK. 1 Publication
    Mutagenesisi112 – 1121Y → F: Complete loss of phosphorylation. 1 Publication

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 497497Latent membrane protein 2PRO_0000116280Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei112 – 1121Phosphotyrosine; by hostSequence Analysis

    Post-translational modificationi

    Isoform LMP2A is phosphorylated on cytoplasmic N-terminal tyrosines residues, possibly by human LYN.1 Publication
    Can be ubiquitinated by human ITCH and WWP2 on the N-terminus in a lysine-independent manner.1 Publication

    Keywords - PTMi

    Phosphoprotein, Ubl conjugation

    Interactioni

    Subunit structurei

    Isoform LMP2A cytoplasmic N-terminal domain interacts with human SRC family protein tyrosine kinases SYK and LYN. Binds human ITCH, WWP2 and NEDD4L.2 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    ITCHQ96J022EBI-7181113,EBI-1564678From a different organism.

    Protein-protein interaction databases

    IntActiP13285. 10 interactions.
    MINTiMINT-6768292.

    Structurei

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    1UXSX-ray1.55C236-244[»]
    1UXWX-ray1.71C236-244[»]
    2JO9NMR-B54-62[»]
    3BVNX-ray2.55C/F236-244[»]
    3REWX-ray1.90C/F426-434[»]
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiP13285.

    Topological domain

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Topological domaini1 – 123123CytoplasmicSequence AnalysisAdd
    BLAST
    Topological domaini145 – 1473ExtracellularSequence Analysis
    Topological domaini169 – 1779CytoplasmicSequence Analysis
    Topological domaini199 – 21113ExtracellularSequence AnalysisAdd
    BLAST
    Topological domaini233 – 2419CytoplasmicSequence Analysis
    Topological domaini263 – 2675ExtracellularSequence Analysis
    Topological domaini289 – 2968CytoplasmicSequence Analysis
    Topological domaini318 – 3181ExtracellularSequence Analysis
    Topological domaini340 – 35415CytoplasmicSequence AnalysisAdd
    BLAST
    Topological domaini376 – 38813ExtracellularSequence AnalysisAdd
    BLAST
    Topological domaini410 – 42213CytoplasmicSequence AnalysisAdd
    BLAST
    Topological domaini444 – 4496ExtracellularSequence Analysis
    Topological domaini471 – 49727CytoplasmicSequence AnalysisAdd
    BLAST

    Transmembrane

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Transmembranei124 – 14421HelicalSequence AnalysisAdd
    BLAST
    Transmembranei148 – 16821HelicalSequence AnalysisAdd
    BLAST
    Transmembranei178 – 19821HelicalSequence AnalysisAdd
    BLAST
    Transmembranei212 – 23221HelicalSequence AnalysisAdd
    BLAST
    Transmembranei242 – 26221HelicalSequence AnalysisAdd
    BLAST
    Transmembranei268 – 28821HelicalSequence AnalysisAdd
    BLAST
    Transmembranei297 – 31721HelicalSequence AnalysisAdd
    BLAST
    Transmembranei319 – 33921HelicalSequence AnalysisAdd
    BLAST
    Transmembranei355 – 37521HelicalSequence AnalysisAdd
    BLAST
    Transmembranei389 – 40921HelicalSequence AnalysisAdd
    BLAST
    Transmembranei423 – 44321HelicalSequence AnalysisAdd
    BLAST
    Transmembranei450 – 47021HelicalSequence AnalysisAdd
    BLAST

    Family & Domainsi

    Motif

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Motifi97 – 1015PPPPY WW-binding

    Sequence similaritiesi

    Belongs to the herpesviridae LMP-2 family.Curated

    Keywords - Domaini

    Transmembrane, Transmembrane helix

    Family and domain databases

    InterProiIPR010881. Herpes_LMP2.
    [Graphical view]
    PfamiPF07415. Herpes_LMP2. 1 hit.
    [Graphical view]

    Sequences (2)i

    Sequence statusi: Complete.

    This entry describes 2 isoformsi produced by alternative splicing. Align

    Isoform LMP2A (identifier: P13285-1) [UniParc]FASTAAdd to Basket

    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.

    « Hide

    MGSLEMVPMG AGPPSPGGDP DGYDGGNNSQ YPSASGSSGN TPTPPNDEER    50
    ESNEEPPPPY EDPYWGNGDR HSDYQPLGTQ DQSLYLGLQH DGNDGLPPPP 100
    YSPRDDSSQH IYEEAGRGSM NPVCLPVIVA PYLFWLAAIA ASCFTASVST 150
    VVTATGLALS LLLLAAVASS YAAAQRKLLT PVTVLTAVVT FFAICLTWRI 200
    EDPPFNSLLF ALLAAAGGLQ GIYVLVMLVL LILAYRRRWR RLTVCGGIMF 250
    LACVLVLIVD AVLQLSPLLG AVTVVSMTLL LLAFVLWLSS PGGLGTLGAA 300
    LLTLAAALAL LASLILGTLN LTTMFLLMLL WTLVVLLICS SCSSCPLSKI 350
    LLARLFLYAL ALLLLASALI AGGSILQTNF KSLSSTEFIP NLFCMLLLIV 400
    AGILFILAIL TEWGSGNRTY GPVFMCLGGL LTMVAGAVWL TVMSNTLLSA 450
    WILTAGFLIF LIGFALFGVI RCCRYCCYYC LTLESEERPP TPYRNTV 497
    Length:497
    Mass (Da):53,011
    Last modified:January 1, 1990 - v1
    Checksum:iF4DC9BB3C1FD83F1
    GO
    Isoform LMP2B (identifier: P13285-2) [UniParc]FASTAAdd to Basket

    Also known as: TP2

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

    Show »
    Length:378
    Mass (Da):40,383
    Checksum:i43526142FFAEE1DC
    GO

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei1 – 119119Missing in isoform LMP2B. 1 PublicationVSP_016139Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    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.
    PIRiA30178. WMBELM.
    RefSeqiYP_401631.1. NC_007605.1.

    Genome annotation databases

    GeneIDi17494212.

    Keywords - Coding sequence diversityi

    Alternative splicing

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    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.
    PIRi A30178. WMBELM.
    RefSeqi YP_401631.1. NC_007605.1.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    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 [» ]
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    IntActi P13285. 10 interactions.
    MINTi MINT-6768292.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    GeneIDi 17494212.

    Miscellaneous databases

    EvolutionaryTracei P13285.

    Family and domain databases

    InterProi IPR010881. Herpes_LMP2.
    [Graphical view ]
    Pfami PF07415. Herpes_LMP2. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    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. 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.

    Entry informationi

    Entry nameiLMP2_EBVB9
    AccessioniPrimary (citable) accession number: P13285
    Secondary accession number(s): Q777H4, Q8AZK9
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: January 1, 1990
    Last sequence update: January 1, 1990
    Last modified: October 1, 2014
    This is version 86 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programViral Protein Annotation Program

    Miscellaneousi

    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.

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    2. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3