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P22366

- MYD88_MOUSE

UniProt

P22366 - MYD88_MOUSE

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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

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 - Biological processi

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

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
Complete GO annotation...

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

BgeeiP22366.
CleanExiMM_MYD88.
ExpressionAtlasiP22366. baseline and differential.
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

        10         20         30         40         50
MSAGDPRVGS GSLDSFMFSI PLVALNVGVR RRLSLFLNPR TPVAADWTLL
60 70 80 90 100
AEEMGFEYLE IRELETRPDP TRSLLDAWQG RSGASVGRLL ELLALLDRED
110 120 130 140 150
ILKELKSRIE EDCQKYLGKQ QNQESEKPLQ VARVESSVPQ TKELGGITTL
160 170 180 190 200
DDPLGQTPEL FDAFICYCPN DIEFVQEMIR QLEQTDYRLK LCVSDRDVLP
210 220 230 240 250
GTCVWSIASE LIEKRCRRMV VVVSDDYLQS KECDFQTKFA LSLSPGVQQK
260 270 280 290
RLIPIKYKAM KKDFPSILRF ITICDYTNPC TKSWFWTRLA KALSLP

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

Bgeei P22366.
CleanExi MM_MYD88.
ExpressionAtlasi P22366. baseline and differential.
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

« Hide 'large scale' publications
  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 29, 2014
This is version 142 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