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Protein

Myeloid differentiation primary response protein MyD88

Gene

Myd88

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: 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 - Molecular functioni

GO - Biological processi

  • 3'-UTR-mediated mRNA stabilization Source: MGI
  • apoptotic process Source: MGI
  • cell surface receptor signaling pathway Source: MGI
  • cellular response to oxidised low-density lipoprotein particle stimulus Source: ARUK-UCL
  • defense response to Gram-positive bacterium Source: UniProtKB
  • establishment of endothelial intestinal barrier Source: MGI
  • immune response Source: MGI
  • immunoglobulin mediated immune response Source: MGI
  • induced systemic resistance Source: MGI
  • inflammatory response Source: MGI
  • JNK cascade Source: Ensembl
  • lipopolysaccharide-mediated signaling pathway Source: MGI
  • MyD88-dependent toll-like receptor signaling pathway Source: MGI
  • negative regulation of growth of symbiont in host Source: MGI
  • positive regulation of chemokine biosynthetic process Source: MGI
  • positive regulation of cytokine production involved in inflammatory response Source: ARUK-UCL
  • positive regulation of gene expression Source: ARUK-UCL
  • positive regulation of I-kappaB kinase/NF-kappaB signaling Source: MGI
  • positive regulation of interleukin-17 production Source: BHF-UCL
  • positive regulation of interleukin-23 production Source: BHF-UCL
  • positive regulation of interleukin-6 production Source: BHF-UCL
  • positive regulation of JNK cascade Source: MGI
  • positive regulation of lymphocyte proliferation Source: MGI
  • positive regulation of NF-kappaB transcription factor activity Source: MGI
  • positive regulation of smooth muscle cell proliferation Source: Ensembl
  • positive regulation of tumor necrosis factor production Source: MGI
  • positive regulation of type I interferon production Source: MGI
  • regulation of cell proliferation Source: MGI
  • regulation of chemokine (C-X-C motif) ligand 1 production Source: MGI
  • regulation of chemokine (C-X-C motif) ligand 2 production Source: MGI
  • regulation of gene expression Source: MGI
  • regulation of inflammatory response Source: BHF-UCL
  • regulation of interleukin-6 production Source: MGI
  • regulation of neutrophil migration Source: MGI
  • regulation of tumor necrosis factor production Source: MGI
  • response to interleukin-1 Source: MGI
  • response to lipopolysaccharide Source: MGI
  • response to molecule of fungal origin Source: MGI
  • response to peptidoglycan Source: MGI
  • response to virus Source: MGI
  • Toll signaling pathway Source: Ensembl
  • transmembrane receptor protein serine/threonine kinase signaling pathway Source: MGI
  • type I interferon biosynthetic process Source: MGI
  • type I interferon signaling pathway Source: MGI

Keywordsi

Biological processImmunity, Inflammatory response, Innate immunity

Enzyme and pathway databases

ReactomeiR-MMU-1257604. PIP3 activates AKT signaling.
R-MMU-1810476. RIP-mediated NFkB activation via ZBP1.
R-MMU-209543. p75NTR recruits signalling complexes.
R-MMU-3134963. DEx/H-box helicases activate type I IFN and inflammatory cytokines production.
R-MMU-445989. TAK1 activates NFkB by phosphorylation and activation of IKKs complex.
R-MMU-446652. Interleukin-1 family signaling.
R-MMU-6811558. PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
R-MMU-933541. TRAF6 mediated IRF7 activation.
R-MMU-933542. TRAF6 mediated NF-kB activation.
R-MMU-975110. TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling.
R-MMU-975138. TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation.
R-MMU-975155. MyD88 dependent cascade initiated on endosome.

Names & Taxonomyi

Protein namesi
Recommended name:
Myeloid differentiation primary response protein MyD88
Gene namesi
Name:Myd88
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 9

Organism-specific databases

MGIiMGI:108005. Myd88.

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

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)DescriptionActionsGraphical viewLength
Mutagenesisi56F → N: Prevents dimerization of death domains and activation of JNK and NF-kappa-B. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000966671 – 296Myeloid differentiation primary response protein MyD88Add BLAST296

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei244PhosphoserineBy similarity1

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiP22366.
PaxDbiP22366.
PeptideAtlasiP22366.
PRIDEiP22366.

PTM databases

iPTMnetiP22366.
PhosphoSitePlusiP22366.

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

BgeeiENSMUSG00000032508.
CleanExiMM_MYD88.
ExpressionAtlasiP22366. baseline and differential.
GenevisibleiP22366. MM.

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. Interacts (via TIR domain) with DHX9 (via H2A and OB-fold regions); this interaction is direct (By similarity).By similarity6 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

Protein-protein interaction databases

BioGridi201639. 32 interactors.
DIPiDIP-34957N.
IntActiP22366. 19 interactors.
STRINGi10090.ENSMUSP00000035092.

Structurei

3D structure databases

ProteinModelPortaliP22366.
SMRiP22366.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini54 – 109DeathPROSITE-ProRule annotationAdd BLAST56
Domaini159 – 296TIRPROSITE-ProRule annotationAdd BLAST138

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni110 – 155Intermediate domainAdd BLAST46

Domaini

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

Phylogenomic databases

eggNOGiENOG410IIN8. Eukaryota.
ENOG410ZIY0. LUCA.
GeneTreeiENSGT00510000048324.
HOGENOMiHOG000068971.
HOVERGENiHBG052547.
InParanoidiP22366.
KOiK04729.
OMAiRCKRMVV.
OrthoDBiEOG091G0NDI.
PhylomeDBiP22366.
TreeFamiTF326264.

Family and domain databases

CDDicd08312. Death_MyD88. 1 hit.
Gene3Di3.40.50.10140. 1 hit.
InterProiView protein in InterPro
IPR011029. DEATH-like_dom.
IPR000488. Death_domain.
IPR034249. MyD88_Death.
IPR017281. Myelin_different_resp_MyD88.
IPR000157. TIR_dom.
PfamiView protein in Pfam
PF00531. Death. 1 hit.
PF01582. TIR. 1 hit.
PIRSFiPIRSF037756. MyD88. 1 hit.
SMARTiView protein in SMART
SM00005. DEATH. 1 hit.
SM00255. TIR. 1 hit.
SUPFAMiSSF47986. SSF47986. 1 hit.
SSF52200. SSF52200. 1 hit.
PROSITEiView protein in PROSITE
PS50017. DEATH_DOMAIN. 1 hit.
PS50104. TIR. 1 hit.

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

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 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti51A → P in AAC53013 (PubMed:9013863).Curated1
Sequence conflicti51A → P in CAA35762 (PubMed:2374694).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_038888110 – 155Missing in isoform 2. CuratedAdd BLAST46

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
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

Similar proteinsi

Entry informationi

Entry nameiMYD88_MOUSE
AccessioniPrimary (citable) accession number: P22366
Secondary accession number(s): O35916
Entry historyiIntegrated into UniProtKB/Swiss-Prot: August 1, 1991
Last sequence update: March 27, 2002
Last modified: September 27, 2017
This is version 166 of the entry and version 3 of the sequence. See 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