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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
  • cell surface receptor signaling pathway Source: MGI
  • cytokine-mediated signaling pathway Source: Ensembl
  • 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 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
Complete GO annotation...

Keywords - Biological processi

Immunity, Inflammatory response, Innate immunity

Enzyme and pathway databases

ReactomeiR-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 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 lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 9

Organism-specific databases

MGIiMGI:108005. Myd88.

Subcellular locationi

GO - Cellular componenti

  • cytoplasm Source: MGI
  • cytosol Source: BHF-UCL
  • plasma membrane Source: BHF-UCL
  • postsynaptic density Source: Ensembl
  • 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

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei244 – 2441PhosphoserineBy similarity

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiP22366.
MaxQBiP22366.
PaxDbiP22366.
PeptideAtlasiP22366.
PRIDEiP22366.

PTM databases

iPTMnetiP22366.
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

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 PIK3AP1.6 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

GO - Molecular functioni

Protein-protein interaction databases

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

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

eggNOGiENOG410IIN8. Eukaryota.
ENOG410ZIY0. LUCA.
GeneTreeiENSGT00510000048324.
HOGENOMiHOG000068971.
HOVERGENiHBG052547.
InParanoidiP22366.
KOiK04729.
OMAiRCKRMVV.
OrthoDBiEOG091G0NDI.
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. 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)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:
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

Cross-referencesi

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.

3D structure databases

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

Protein-protein interaction databases

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

PTM databases

iPTMnetiP22366.
PhosphoSiteiP22366.

Proteomic databases

EPDiP22366.
MaxQBiP22366.
PaxDbiP22366.
PeptideAtlasiP22366.
PRIDEiP22366.

Protocols and materials databases

DNASUi17874.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

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

Organism-specific databases

CTDi4615.
MGIiMGI:108005. Myd88.

Phylogenomic databases

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

Enzyme and pathway databases

ReactomeiR-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 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.

Miscellaneous databases

PROiP22366.
SOURCEiSearch...

Gene expression databases

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

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]
ProtoNetiSearch...

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: September 7, 2016
This is version 158 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

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.