P22366 (MYD88_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Myeloid differentiation primary response protein MyD88

Gene names

Name:

Myd88

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	296 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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. Ref.4 Ref.5 Ref.6 Ref.7 Ref.9 Ref.10
Subunit structure	Homodimer. Also forms heterodimers with TIRAP. Binds to TLR2, TLR4, IRAK1, IRAK2 and IRAK4 via their respective TIR domains. Interacts with IL1RL1. Interacts with IL18R1. Interacts with BMX and IRF7 By similarity. Interacts with LRRFIP1 and LRRFIP2; this interaction positively regulates Toll-like receptor (TLR) signaling in response to agonist By similarity. Interacts with FLII By similarity. LRRFIP1 and LRRFIP2 compete with FLII for MYD88-binding By similarity. 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. Ref.5 Ref.6 Ref.7 Ref.8 Ref.9
Subcellular location	Cytoplasm Ref.9.
Tissue specificity	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. Ref.1 Ref.4 Ref.5 Ref.7
Induction	By interleukin-6. Ref.4
Domain	The intermediate domain (ID) is required for the phosphorylation and activation of IRAK.
Disruption phenotype	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. Ref.6 Ref.10
Sequence similarities	Contains 1 death domain. Contains 1 TIR domain.
Sequence caution	The sequence CAA35762.1 differs from that shown. Reason: Erroneous initiation.

Ontologies

Keywords
Biological process	Immunity Inflammatory response Innate immunity
Cellular component	Cytoplasm
Coding sequence diversity	Alternative splicing
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	JNK cascade Inferred from electronic annotation. Source: Compara MyD88-dependent toll-like receptor signaling pathway Inferred from mutant phenotype PubMed 12872135PubMed 14764662. Source: MGI Toll signaling pathway Inferred from electronic annotation. Source: Compara cytokine-mediated signaling pathway Inferred from electronic annotation. Source: Compara defense response to Gram-positive bacterium Inferred from mutant phenotype PubMed 11067888. Source: MGI immunoglobulin mediated immune response Inferred from mutant phenotype PubMed 15800576. Source: MGI inflammatory response Inferred from electronic annotation. Source: UniProtKB-KW innate immune response Inferred from electronic annotation. Source: UniProtKB-KW lipopolysaccharide-mediated signaling pathway Inferred from mutant phenotype PubMed 12855817. Source: MGI negative regulation of growth of symbiont in host Inferred from mutant phenotype PubMed 11067888. Source: MGI positive regulation of I-kappaB kinase/NF-kappaB cascade Inferred from mutant phenotype PubMed 12855817. Source: MGI positive regulation of JNK cascade Inferred from mutant phenotype PubMed 12855817. Source: MGI positive regulation of NF-kappaB transcription factor activity Inferred from mutant phenotype PubMed 12855817. Source: MGI positive regulation of chemokine biosynthetic process Inferred from genetic interaction PubMed 12855817. Source: MGI positive regulation of interleukin-17 production Inferred from mutant phenotype PubMed 18203139. Source: BHF-UCL positive regulation of interleukin-23 production Inferred from mutant phenotype PubMed 18203139. Source: BHF-UCL positive regulation of interleukin-6 production Inferred from mutant phenotype PubMed 18203139. Source: BHF-UCL positive regulation of lymphocyte proliferation Inferred from mutant phenotype PubMed 10607756. Source: MGI positive regulation of smooth muscle cell proliferation Inferred from electronic annotation. Source: Compara positive regulation of transcription from RNA polymerase II promoter Inferred from electronic annotation. Source: Compara positive regulation of tumor necrosis factor production Inferred from mutant phenotype PubMed 10607756PubMed 11067888PubMed 12719478PubMed 12872135. Source: MGI regulation of inflammatory response Inferred from mutant phenotype PubMed 18203139. Source: BHF-UCL response to molecule of fungal origin Inferred from mutant phenotype PubMed 12719478. Source: MGI response to peptidoglycan Inferred from mutant phenotype PubMed 10607756. Source: MGI response to virus Inferred from mutant phenotype PubMed 14993594PubMed 15800576. Source: MGI transmembrane receptor protein serine/threonine kinase signaling pathway Traceable author statement PubMed 10465784. Source: MGI type I interferon biosynthetic process Inferred from mutant phenotype PubMed 15800576. Source: MGI
Cellular_component	cytosol Inferred from direct assay PubMed 16751103. Source: BHF-UCL plasma membrane Inferred from direct assay PubMed 16751103. Source: BHF-UCL postsynaptic density Inferred from electronic annotation. Source: Compara protein complex Inferred from electronic annotation. Source: Compara
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Btk	P35991	2	EBI-525108,EBI-625119
Cblb	Q3TTA7	2	EBI-525108,EBI-3649276
Irak1	Q62406	2	EBI-525108,EBI-448533

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P22366-1)

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.

Note: Major isoform.

Isoform 2 (identifier: P22366-2)

Also known as: MyD88S;

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

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 296	296	Myeloid differentiation primary response protein MyD88		PRO_0000096667
Regions
	Domain	54 – 109	56	Death
	Domain	159 – 296	138	TIR
	Region	110 – 155	46	Intermediate domain
Natural variations
	Alternative sequence	110 – 155	46	Missing in isoform 2.		VSP_038888
Experimental info
	Mutagenesis	56	1	F → N: Prevents dimerization of death domains and activation of JNK and NF-kappa-B. Ref.5
	Sequence conflict	51	1	A → P in AAC53013. Ref.1
	Sequence conflict	51	1	A → P in CAA35762. Ref.4

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (MyD88L) [UniParc]. Last modified March 27, 2002. Version 3. Checksum: 393A75C3723FFE69	FASTA	296	33,753
	10 20 30 40 50 60 MSAGDPRVGS GSLDSFMFSI PLVALNVGVR RRLSLFLNPR TPVAADWTLL AEEMGFEYLE 70 80 90 100 110 120 IRELETRPDP TRSLLDAWQG RSGASVGRLL ELLALLDRED ILKELKSRIE EDCQKYLGKQ 130 140 150 160 170 180 QNQESEKPLQ VARVESSVPQ TKELGGITTL DDPLGQTPEL FDAFICYCPN DIEFVQEMIR 190 200 210 220 230 240 QLEQTDYRLK LCVSDRDVLP GTCVWSIASE LIEKRCRRMV VVVSDDYLQS KECDFQTKFA 250 260 270 280 290 LSLSPGVQQK RLIPIKYKAM KKDFPSILRF ITICDYTNPC TKSWFWTRLA KALSLP
	Isoform 2 (MyD88S) [UniParc]. Checksum: B8A0F358402EBC1E	FASTA	250	28,683
	10 20 30 40 50 60 MSAGDPRVGS GSLDSFMFSI PLVALNVGVR RRLSLFLNPR TPVAADWTLL AEEMGFEYLE 70 80 90 100 110 120 IRELETRPDP TRSLLDAWQG RSGASVGRLL ELLALLDRED ILKELKSRIQ TPELFDAFIC 130 140 150 160 170 180 YCPNDIEFVQ EMIRQLEQTD YRLKLCVSDR DVLPGTCVWS IASELIEKRC RRMVVVVSDD 190 200 210 220 230 240 YLQSKECDFQ TKFALSLSPG VQQKRLIPIK YKAMKKDFPS ILRFITICDY TNPCTKSWFW 250 TRLAKALSLP

References

	« Hide 'large scale' referencesShow 'large scale' references »
[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]	"Genetic structure and chromosomal mapping of MyD88." Hardiman G., Jenkins N.A., Copeland N.G., Gilbert D.J., Garcia D.K., Naylor S.L., Kastelein R.A., Bazan J.F. Genomics 45:332-339(1997) [PubMed] [Europe PMC] [Abstract] 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]	"MyD88, an adapter protein involved in interleukin-1 signaling." Burns K., Martinon F., Esslinger C., Pahl H., Schneider P., Bodmer J.-L., Di Marco F., French L., Tschopp J. J. Biol. Chem. 273:12203-12209(1998) [PubMed] [Europe PMC] [Abstract] 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]	"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.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	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.
IPI	IPI00127375. IPI00955716.
PIR	S11226.
RefSeq	NP_034981.1. NM_010851.2.
UniGene	Mm.213003.
3D structure databases
ProteinModelPortal	P22366.
SMR	P22366. Positions 20-118, 158-296.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-34957N.
IntAct	P22366. 11 interactions.
PTM databases
PhosphoSite	P22366.
Proteomic databases
PaxDb	P22366.
PRIDE	P22366.
Protocols and materials databases
DNASU	17874.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000035092; ENSMUSP00000035092; ENSMUSG00000032508.
GeneID	17874.
KEGG	mmu:17874.
Organism-specific databases
CTD	4615.
MGI	MGI:108005. Myd88.
Phylogenomic databases
eggNOG	NOG70664.
HOGENOM	HOG000068971.
HOVERGEN	HBG052547.
InParanoid	P22366.
KO	K04729.
OMA	RCKRMVV.
OrthoDB	EOG4GXFNH.
Gene expression databases
ArrayExpress	P22366.
Bgee	P22366.
CleanEx	MM_MYD88.
Genevestigator	P22366.
GermOnline	ENSMUSG00000032508. Mus musculus.
Family and domain databases
Gene3D	1.10.533.10. 1 hit.
InterPro	IPR011029. DEATH-like_dom. IPR000488. Death_domain. IPR017281. Myelin_different_resp_MyD88. IPR000157. TIR_dom. [Graphical view]
Pfam	PF00531. Death. 1 hit. PF01582. TIR. 1 hit. [Graphical view]
PIRSF	PIRSF037756. MyD88. 1 hit.
SMART	SM00005. DEATH. 1 hit. SM00255. TIR. 1 hit. [Graphical view]
SUPFAM	SSF47986. DEATH_like. 1 hit. SSF52200. TIR. 1 hit.
PROSITE	PS50017. DEATH_DOMAIN. 1 hit. PS50104. TIR. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	292657.
SOURCE	Search...

Entry information

Entry name

MYD88_MOUSE

Accession

Primary (citable) accession number: P22366
Secondary accession number(s): O35916

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 1, 1991
Last sequence update:	March 27, 2002
Last modified:	April 3, 2013
This is version 126 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program