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P22366

- MYD88_MOUSE

UniProt

P22366 - MYD88_MOUSE

Protein

Myeloid differentiation primary response protein MyD88

Gene

Myd88

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 141 (01 Oct 2014)
      Sequence version 3 (27 Mar 2002)
      Previous versions | rss
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    Functioni

    Adapter protein involved in the Toll-like receptor and IL-1 receptor signaling pathway in the innate immune response. Acts via IRAK1, IRAK2, IRF7 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. Increases IL-8 transcription. Involved in IL-18-mediated signaling pathway. Isoform 2 is defective in its ability to induce IRAK phosphorylation and NF-kappa-B activation and can function as a negative regulator of activation by IL-1 or lipopolysaccharide (LPS). Activates IRF1 resulting in its rapid migration into the nucleus to mediate an efficient induction of IFN-beta, NOS2/INOS, and IL12A genes. MyD88-mediated signaling in intestinal epithelial cells is crucial for maintenance of gut homeostasis and controls the expression of the antimicrobial lectin REG3G in the small intestine.8 Publications

    GO - Molecular functioni

    1. protein binding Source: UniProtKB

    GO - Biological processi

    1. cell surface receptor signaling pathway Source: MGI
    2. cytokine-mediated signaling pathway Source: Ensembl
    3. defense response to Gram-positive bacterium Source: UniProtKB
    4. establishment of endothelial intestinal barrier Source: MGI
    5. immune response Source: MGI
    6. immunoglobulin mediated immune response Source: MGI
    7. inflammatory response Source: UniProtKB-KW
    8. innate immune response Source: UniProtKB-KW
    9. JNK cascade Source: Ensembl
    10. lipopolysaccharide-mediated signaling pathway Source: MGI
    11. MyD88-dependent toll-like receptor signaling pathway Source: MGI
    12. negative regulation of growth of symbiont in host Source: MGI
    13. positive regulation of chemokine biosynthetic process Source: MGI
    14. positive regulation of I-kappaB kinase/NF-kappaB signaling Source: MGI
    15. positive regulation of interleukin-17 production Source: BHF-UCL
    16. positive regulation of interleukin-23 production Source: BHF-UCL
    17. positive regulation of interleukin-6 production Source: BHF-UCL
    18. positive regulation of JNK cascade Source: MGI
    19. positive regulation of lymphocyte proliferation Source: MGI
    20. positive regulation of NF-kappaB transcription factor activity Source: MGI
    21. positive regulation of smooth muscle cell proliferation Source: Ensembl
    22. positive regulation of transcription from RNA polymerase II promoter Source: Ensembl
    23. positive regulation of tumor necrosis factor production Source: MGI
    24. regulation of cell proliferation Source: MGI
    25. regulation of inflammatory response Source: BHF-UCL
    26. response to lipopolysaccharide Source: MGI
    27. response to molecule of fungal origin Source: MGI
    28. response to peptidoglycan Source: MGI
    29. response to virus Source: MGI
    30. Toll signaling pathway Source: Ensembl
    31. transmembrane receptor protein serine/threonine kinase signaling pathway Source: MGI
    32. type I interferon biosynthetic process Source: MGI

    Keywords - Biological processi

    Immunity, Inflammatory response, Innate immunity

    Enzyme and pathway databases

    ReactomeiREACT_198521. TRAF6 mediated IRF7 activation.
    REACT_198527. TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling.
    REACT_202898. TRAF6 mediated NF-kB activation.
    REACT_214670. p75NTR recruits signalling complexes.
    REACT_219800. TAK1 activates NFkB by phosphorylation and activation of IKKs complex.
    REACT_222971. RIP-mediated NFkB activation via ZBP1.
    REACT_224208. Interleukin-1 signaling.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Myeloid differentiation primary response protein MyD88
    Gene namesi
    Name:Myd88
    OrganismiMus musculus (Mouse)
    Taxonomic identifieri10090 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
    ProteomesiUP000000589: Chromosome 9

    Organism-specific databases

    MGIiMGI:108005. Myd88.

    Subcellular locationi

    Cytoplasm 1 Publication

    GO - Cellular componenti

    1. cytoplasm Source: MGI
    2. cytosol Source: BHF-UCL
    3. plasma membrane Source: BHF-UCL
    4. postsynaptic density Source: Ensembl
    5. protein complex Source: Ensembl

    Keywords - Cellular componenti

    Cytoplasm

    Pathology & Biotechi

    Disruption phenotypei

    Mice appear normal, but display loss of activation of NF-kappa-B in response to IL-1 or IL-18. They show no increase in interferon gamma production or in stimulation of natural killer cell activity in response to IL-18. They are impaired in production of cytokines in response to IL-1. They have defects in proinflammatory gene expression and leukocyte recruitment after brain injury. Mice have a diminished capacity to kill L.monocytogenes in the lumen of the distal small intestine and express markedly diminished levels of REG3G.3 Publications

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi56 – 561F → N: Prevents dimerization of death domains and activation of JNK and NF-kappa-B. 1 Publication

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 296296Myeloid differentiation primary response protein MyD88PRO_0000096667Add
    BLAST

    Proteomic databases

    MaxQBiP22366.
    PaxDbiP22366.
    PRIDEiP22366.

    PTM databases

    PhosphoSiteiP22366.

    Expressioni

    Tissue specificityi

    Detected in bone marrow. Isoform 1 is expressed in testis, kidney, lung, ovary, adrenal gland, prostate, thymus and heart, and weakly in skeletal muscle, liver, spleen and brain. Isoform 2 is mainly expressed in the spleen and weakly in brain.5 Publications

    Inductioni

    By interleukin-6.1 Publication

    Gene expression databases

    ArrayExpressiP22366.
    BgeeiP22366.
    CleanExiMM_MYD88.
    GenevestigatoriP22366.

    Interactioni

    Subunit structurei

    Homodimer. Also forms heterodimers with TIRAP. Binds to TLR2, TLR4, IRAK1, IRAK2 and IRAK4 via their respective TIR domains. Interacts with IL18R1. Interacts with BMX, IL1RL1, IKBKE and IRF7. Interacts with LRRFIP1 and LRRFIP2; this interaction positively regulates Toll-like receptor (TLR) signaling in response to agonist. Interacts with FLII. LRRFIP1 and LRRFIP2 compete with FLII for MYD88-binding. Interacts with IRF1. Upon IL1B treatment, forms a complex with PELI1, IRAK1, IRAK4 and TRAF6; this complex recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation. Direct binding of SMAD6 to PELI1 prevents the complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression. May interact with PIK3AP1.6 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    BtkP359912EBI-525108,EBI-625119
    CblbQ3TTA72EBI-525108,EBI-3649276
    Irak1Q624062EBI-525108,EBI-448533
    Irak4Q8R4K24EBI-525108,EBI-3842721
    Pik3ap1Q9EQ322EBI-525108,EBI-643949

    Protein-protein interaction databases

    BioGridi201639. 29 interactions.
    DIPiDIP-34957N.
    IntActiP22366. 19 interactions.

    Structurei

    3D structure databases

    ProteinModelPortaliP22366.
    SMRiP22366. Positions 20-118, 158-296.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini54 – 10956DeathPROSITE-ProRule annotationAdd
    BLAST
    Domaini159 – 296138TIRPROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni110 – 15546Intermediate domainAdd
    BLAST

    Domaini

    The intermediate domain (ID) is required for the phosphorylation and activation of IRAK.

    Sequence similaritiesi

    Contains 1 death domain.PROSITE-ProRule annotation
    Contains 1 TIR domain.PROSITE-ProRule annotation

    Phylogenomic databases

    eggNOGiNOG70664.
    HOGENOMiHOG000068971.
    HOVERGENiHBG052547.
    InParanoidiP22366.
    KOiK04729.
    OMAiRCKRMVV.
    OrthoDBiEOG7H792K.
    PhylomeDBiP22366.
    TreeFamiTF326264.

    Family and domain databases

    Gene3Di1.10.533.10. 1 hit.
    3.40.50.10140. 1 hit.
    InterProiIPR011029. DEATH-like_dom.
    IPR000488. Death_domain.
    IPR017281. Myelin_different_resp_MyD88.
    IPR000157. TIR_dom.
    [Graphical view]
    PfamiPF00531. Death. 1 hit.
    PF01582. TIR. 1 hit.
    [Graphical view]
    PIRSFiPIRSF037756. MyD88. 1 hit.
    SMARTiSM00005. DEATH. 1 hit.
    SM00255. TIR. 1 hit.
    [Graphical view]
    SUPFAMiSSF47986. SSF47986. 1 hit.
    SSF52200. SSF52200. 1 hit.
    PROSITEiPS50017. DEATH_DOMAIN. 1 hit.
    PS50104. TIR. 1 hit.
    [Graphical view]

    Sequences (2)i

    Sequence statusi: Complete.

    This entry describes 2 isoformsi produced by alternative splicing. Align

    Isoform 1 (identifier: P22366-1) [UniParc]FASTAAdd to Basket

    Also known as: MyD88L

    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

    MSAGDPRVGS GSLDSFMFSI PLVALNVGVR RRLSLFLNPR TPVAADWTLL    50
    AEEMGFEYLE IRELETRPDP TRSLLDAWQG RSGASVGRLL ELLALLDRED 100
    ILKELKSRIE EDCQKYLGKQ QNQESEKPLQ VARVESSVPQ TKELGGITTL 150
    DDPLGQTPEL FDAFICYCPN DIEFVQEMIR QLEQTDYRLK LCVSDRDVLP 200
    GTCVWSIASE LIEKRCRRMV VVVSDDYLQS KECDFQTKFA LSLSPGVQQK 250
    RLIPIKYKAM KKDFPSILRF ITICDYTNPC TKSWFWTRLA KALSLP 296

    Note: Major isoform.

    Length:296
    Mass (Da):33,753
    Last modified:March 27, 2002 - v3
    Checksum:i393A75C3723FFE69
    GO
    Isoform 2 (identifier: P22366-2) [UniParc]FASTAAdd to Basket

    Also known as: MyD88S

    The sequence of this isoform differs from the canonical sequence as follows:
         110-155: Missing.

    Show »
    Length:250
    Mass (Da):28,683
    Checksum:iB8A0F358402EBC1E
    GO

    Sequence cautioni

    The sequence CAA35762.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti51 – 511A → P in AAC53013. (PubMed:9013863)Curated
    Sequence conflicti51 – 511A → P in CAA35762. (PubMed:2374694)Curated

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei110 – 15546Missing in isoform 2. CuratedVSP_038888Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U84409 mRNA. Translation: AAC53013.1.
    U89023 Genomic DNA. Translation: AAB83958.1.
    BC005591 mRNA. Translation: AAH05591.1.
    BC058787 mRNA. Translation: AAH58787.1.
    X51397 mRNA. Translation: CAA35762.1. Different initiation.
    CCDSiCCDS23612.1. [P22366-1]
    PIRiS11226.
    RefSeqiNP_034981.1. NM_010851.2. [P22366-1]
    UniGeneiMm.213003.

    Genome annotation databases

    EnsembliENSMUST00000035092; ENSMUSP00000035092; ENSMUSG00000032508. [P22366-1]
    GeneIDi17874.
    KEGGimmu:17874.
    UCSCiuc009sar.1. mouse. [P22366-1]

    Keywords - Coding sequence diversityi

    Alternative splicing

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U84409 mRNA. Translation: AAC53013.1 .
    U89023 Genomic DNA. Translation: AAB83958.1 .
    BC005591 mRNA. Translation: AAH05591.1 .
    BC058787 mRNA. Translation: AAH58787.1 .
    X51397 mRNA. Translation: CAA35762.1 . Different initiation.
    CCDSi CCDS23612.1. [P22366-1 ]
    PIRi S11226.
    RefSeqi NP_034981.1. NM_010851.2. [P22366-1 ]
    UniGenei Mm.213003.

    3D structure databases

    ProteinModelPortali P22366.
    SMRi P22366. Positions 20-118, 158-296.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 201639. 29 interactions.
    DIPi DIP-34957N.
    IntActi P22366. 19 interactions.

    PTM databases

    PhosphoSitei P22366.

    Proteomic databases

    MaxQBi P22366.
    PaxDbi P22366.
    PRIDEi P22366.

    Protocols and materials databases

    DNASUi 17874.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSMUST00000035092 ; ENSMUSP00000035092 ; ENSMUSG00000032508 . [P22366-1 ]
    GeneIDi 17874.
    KEGGi mmu:17874.
    UCSCi uc009sar.1. mouse. [P22366-1 ]

    Organism-specific databases

    CTDi 4615.
    MGIi MGI:108005. Myd88.

    Phylogenomic databases

    eggNOGi NOG70664.
    HOGENOMi HOG000068971.
    HOVERGENi HBG052547.
    InParanoidi P22366.
    KOi K04729.
    OMAi RCKRMVV.
    OrthoDBi EOG7H792K.
    PhylomeDBi P22366.
    TreeFami TF326264.

    Enzyme and pathway databases

    Reactomei REACT_198521. TRAF6 mediated IRF7 activation.
    REACT_198527. TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling.
    REACT_202898. TRAF6 mediated NF-kB activation.
    REACT_214670. p75NTR recruits signalling complexes.
    REACT_219800. TAK1 activates NFkB by phosphorylation and activation of IKKs complex.
    REACT_222971. RIP-mediated NFkB activation via ZBP1.
    REACT_224208. Interleukin-1 signaling.

    Miscellaneous databases

    NextBioi 292657.
    PROi P22366.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi P22366.
    Bgeei P22366.
    CleanExi MM_MYD88.
    Genevestigatori P22366.

    Family and domain databases

    Gene3Di 1.10.533.10. 1 hit.
    3.40.50.10140. 1 hit.
    InterProi IPR011029. DEATH-like_dom.
    IPR000488. Death_domain.
    IPR017281. Myelin_different_resp_MyD88.
    IPR000157. TIR_dom.
    [Graphical view ]
    Pfami PF00531. Death. 1 hit.
    PF01582. TIR. 1 hit.
    [Graphical view ]
    PIRSFi PIRSF037756. MyD88. 1 hit.
    SMARTi SM00005. DEATH. 1 hit.
    SM00255. TIR. 1 hit.
    [Graphical view ]
    SUPFAMi SSF47986. SSF47986. 1 hit.
    SSF52200. SSF52200. 1 hit.
    PROSITEi PS50017. DEATH_DOMAIN. 1 hit.
    PS50104. TIR. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "The cloning and characterization of human MyD88: a member of an IL-1 receptor related family."
      Bonnert T.P., Garka K.E., Parnet P., Sonoda G., Testa J.R., Sims J.E.
      FEBS Lett. 402:81-84(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY.
    2. Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
      Tissue: Myeloid leukemia cell.
    3. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
      The MGC Project Team
      Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
      Strain: C57BL/6J.
      Tissue: Mammary gland and Olfactory epithelium.
    4. "Nucleotide sequence and expression of a cDNA encoding MyD88, a novel myeloid differentiation primary response gene induced by IL6."
      Lord K.A., Hoffman-Liebermann B., Liebermann D.A.
      Oncogene 5:1095-1097(1990) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 18-296 (ISOFORM 1), FUNCTION, INDUCTION, TISSUE SPECIFICITY.
    5. Cited for: FUNCTION, SUBUNIT, TISSUE SPECIFICITY, MUTAGENESIS OF PHE-56.
      Tissue: Bone marrow.
    6. "Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function."
      Adachi O., Kawai T., Takeda K., Matsumoto M., Tsutsui H., Sakagami M., Nakanishi K., Akira S.
      Immunity 9:143-150(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, INTERACTION WITH IL18R1, DISRUPTION PHENOTYPE.
    7. "Regulation of interleukin-1- and lipopolysaccharide-induced NF-kappaB activation by alternative splicing of MyD88."
      Janssens S., Burns K., Tschopp J., Beyaert R.
      Curr. Biol. 12:467-471(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: ALTERNATIVE SPLICING, IDENTIFICATION OF ISOFORM 2, FUNCTION, SUBUNIT, TISSUE SPECIFICITY.
    8. "Smad6 negatively regulates interleukin 1-receptor-Toll-like receptor signaling through direct interaction with the adaptor Pellino-1."
      Choi K.C., Lee Y.S., Lim S., Choi H.K., Lee C.H., Lee E.K., Hong S., Kim I.H., Kim S.J., Park S.H.
      Nat. Immunol. 7:1057-1065(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: IDENTIFICATION IN COMPLEX WITH IRAK1; IRAK4; TRAF6 AND PELI1.
    9. "Evidence for licensing of IFN-gamma-induced IFN regulatory factor 1 transcription factor by MyD88 in Toll-like receptor-dependent gene induction program."
      Negishi H., Fujita Y., Yanai H., Sakaguchi S., Ouyang X., Shinohara M., Takayanagi H., Ohba Y., Taniguchi T., Honda K.
      Proc. Natl. Acad. Sci. U.S.A. 103:15136-15141(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH IRF1.
    10. "MyD88-mediated signals induce the bactericidal lectin RegIII gamma and protect mice against intestinal Listeria monocytogenes infection."
      Brandl K., Plitas G., Schnabl B., DeMatteo R.P., Pamer E.G.
      J. Exp. Med. 204:1891-1900(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION.
    11. "Signaling through MyD88 regulates leukocyte recruitment after brain injury."
      Babcock A.A., Toft-Hansen H., Owens T.
      J. Immunol. 181:6481-6490(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, DISRUPTION PHENOTYPE.
    12. "The antibacterial lectin RegIIIgamma promotes the spatial segregation of microbiota and host in the intestine."
      Vaishnava S., Yamamoto M., Severson K.M., Ruhn K.A., Yu X., Koren O., Ley R., Wakeland E.K., Hooper L.V.
      Science 334:255-258(2011) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, TISSUE SPECIFICITY, DISRUPTION PHENOTYPE.
    13. "Role for B-cell adapter for PI3K (BCAP) as a signaling adapter linking Toll-like receptors (TLRs) to serine/threonine kinases PI3K/Akt."
      Troutman T.D., Hu W., Fulenchek S., Yamazaki T., Kurosaki T., Bazan J.F., Pasare C.
      Proc. Natl. Acad. Sci. U.S.A. 109:273-278(2012) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH PIK3AP1.

    Entry informationi

    Entry nameiMYD88_MOUSE
    AccessioniPrimary (citable) accession number: P22366
    Secondary accession number(s): O35916
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: August 1, 1991
    Last sequence update: March 27, 2002
    Last modified: October 1, 2014
    This is version 141 of the entry and version 3 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program

    Miscellaneousi

    Keywords - Technical termi

    Complete proteome, Reference proteome

    Documents

    1. MGD cross-references
      Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
    2. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3