Q99836 (MYD88_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Myeloid differentiation primary response protein MyD88

Gene names

Name:

MYD88

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

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. Ref.2 Ref.7 Ref.10 Ref.12
Subunit structure	Homodimer. Also forms heterodimers with TIRAP. Binds to TLR2, TLR4, IRAK1, IRAK2 and IRAK4 via their respective TIR domains. Interacts with IL18R1 By similarity. Interacts with BMX, IL1RL1 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. Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12
Subcellular location	Cytoplasm Ref.7 Ref.8.
Tissue specificity	Ubiquitous. Ref.1
Domain	The intermediate domain (ID) is required for the phosphorylation and activation of IRAK By similarity.
Involvement in disease	Defects in MYD88 are the cause of MYD88 deficiency (MYD88D) [MIM:612260]; also known as recurrent pyogenic bacterial infections due to MYD88 deficiency. Patients suffer from autosomal recessive, life-threatening, often recurrent pyogenic bacterial infections, including invasive pneumococcal disease, and die between 1 and 11 months of age. Surviving patients are otherwise healthy, with normal resistance to other microbes, and their clinical status improved with age. Ref.12 Ref.14
Sequence similarities	Contains 1 death domain. Contains 1 TIR domain.

Ontologies

Keywords
Biological process	Immunity Inflammatory response Innate immunity
Cellular component	Cytoplasm
Coding sequence diversity	Alternative splicing
Disease	Disease mutation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	3'-UTR-mediated mRNA stabilization Inferred from direct assay. Source: BHF-UCL MyD88-dependent toll-like receptor signaling pathway Traceable author statement. Source: Reactome Toll signaling pathway Traceable author statement. Source: Reactome anti-apoptosis Traceable author statement. Source: Reactome cellular response to mechanical stimulus Inferred from expression pattern. Source: UniProtKB inflammatory response Inferred from electronic annotation. Source: UniProtKB-KW innate immune response Traceable author statement. Source: Reactome nerve growth factor receptor signaling pathway Traceable author statement. Source: Reactome positive regulation of I-kappaB kinase/NF-kappaB cascade Inferred from expression pattern. Source: UniProtKB positive regulation of interleukin-17 production Inferred from sequence or structural similarity. Source: BHF-UCL positive regulation of interleukin-23 production Inferred from sequence or structural similarity. Source: BHF-UCL positive regulation of interleukin-6 production Inferred from sequence or structural similarity. Source: BHF-UCL regulation of inflammatory response Inferred from sequence or structural similarity. Source: BHF-UCL response to interleukin-1 Inferred from mutant phenotype. Source: BHF-UCL toll-like receptor 1 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 2 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 4 signaling pathway Traceable author statement. Source: Reactome
Cellular component	cytosol Traceable author statement. Source: Reactome endosome membrane Traceable author statement. Source: Reactome plasma membrane Traceable author statement. Source: Reactome
Molecular function	TIR domain binding Inferred from physical interaction. Source: BHF-UCL death receptor binding Traceable author statement. Source: ProtInc identical protein binding Inferred from physical interaction. Source: IntAct
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
itself		3	EBI-447677,EBI-447677
FADD	Q13158	3	EBI-447677,EBI-494804
SIAH1	Q8IUQ4	3	EBI-447677,EBI-747107
SMAD3	P84022	3	EBI-447677,EBI-347161
SPOP	O43791	6	EBI-447677,EBI-743549
STAP2	Q9UGK3	3	EBI-447677,EBI-1553984
TIRAP	P58753	4	EBI-447677,EBI-528644
TNFRSF13B	O14836	12	EBI-447677,EBI-519160
TXN	P10599	4	EBI-447677,EBI-594644
USP7	Q93009	3	EBI-447677,EBI-302474

Alternative products

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

Isoform 1 (identifier: Q99836-1)

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.

Isoform 2 (identifier: Q99836-2)

The sequence of this isoform differs from the canonical sequence as follows:
     110-154: Missing.

Note: No experimental confirmation available.

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_0000096666

Regions

Domain

54 – 109

56

Death

Domain

159 – 296

138

TIR

Region

110 – 155

46

Intermediate domain By similarity

Natural variations

Alternative sequence

110 – 154

45

Missing in isoform 2.

VSP_038887

Natural variant

93

1

L → P in MYD88D; results in a loss of function. Ref.14

VAR_047953

Natural variant

196

1

R → C in MYD88D; results in a loss of function. Ref.12 Ref.14

VAR_047954

Experimental info

Mutagenesis

196

1

R → A: Reduced interaction with TIRAP, and strongly reduced activity. Strongly reduced interaction with TIRAP; when associated with A-288. Ref.12

Mutagenesis

197

1

D → A: Slightly reduced activity. Ref.12

Mutagenesis

217

1

R → A: Strongly reduced activity. Ref.12

Mutagenesis

282

1

K → A: Slightly reduced activity. Ref.12

Mutagenesis

288

1

R → A: Slightly reduced activity, and reduced interaction with TIRAP. Strongly reduced interaction with TIRAP; when associated with A-196. Ref.12

Sequence conflict

98

1

R → C in AAB49967. Ref.1

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

296

Helix Strand Turn

Details...

Beta strand

161 – 166

6

Helix

169 – 171

3

Helix

172 – 183

12

Beta strand

185 – 187

3

Beta strand

192 – 194

3

Beta strand

197 – 201

5

Helix

209 – 211

3

Helix

212 – 215

4

Beta strand

216 – 222

7

Helix

225 – 229

5

Helix

231 – 243

13

Helix

247 – 250

4

Beta strand

252 – 258

7

Turn

266 – 268

3

Turn

279 – 281

3

Helix

285 – 294

10

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified May 1, 1997. Version 1. Checksum: CEAE3F6B99524333	FASTA	296	33,233
	10 20 30 40 50 60 MAAGGPGAGS AAPVSSTSSL PLAALNMRVR RRLSLFLNVR TQVAADWTAL AEEMDFEYLE 70 80 90 100 110 120 IRQLETQADP TGRLLDAWQG RPGASVGRLL ELLTKLGRDD VLLELGPSIE EDCQKYILKQ 130 140 150 160 170 180 QQEEAEKPLQ VAAVDSSVPR TAELAGITTL DDPLGHMPER FDAFICYCPS DIQFVQEMIR 190 200 210 220 230 240 QLEQTNYRLK LCVSDRDVLP GTCVWSIASE LIEKRCRRMV VVVSDDYLQS KECDFQTKFA 250 260 270 280 290 LSLSPGAHQK RLIPIKYKAM KKEFPSILRF ITVCDYTNPC TKSWFWTRLA KALSLP
	Isoform 2 [UniParc]. Checksum: 1841504370960C90	FASTA	251	28,280
	10 20 30 40 50 60 MAAGGPGAGS AAPVSSTSSL PLAALNMRVR RRLSLFLNVR TQVAADWTAL AEEMDFEYLE 70 80 90 100 110 120 IRQLETQADP TGRLLDAWQG RPGASVGRLL ELLTKLGRDD VLLELGPSIG HMPERFDAFI 130 140 150 160 170 180 CYCPSDIQFV QEMIRQLEQT NYRLKLCVSD RDVLPGTCVW SIASELIEKR CRRMVVVVSD 190 200 210 220 230 240 DYLQSKECDF QTKFALSLSP GAHQKRLIPI KYKAMKKEFP SILRFITVCD YTNPCTKSWF 250 WTRLAKALSL P

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Molecular characterization and modular analysis of human MyD88." Hardiman G., Rock F.L., Balasubramanian S., Kastelein R.A., Bazan J.F. Oncogene 13:2467-2475(1996) [PubMed: 8957090] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY. Tissue: Dendritic cell.
[2]	"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: 9013863] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION. Tissue: Epidermal carcinoma.
[3]	"Natural selection in the TLR-related genes in the course of primate evolution." Nakajima T., Ohtani H., Satta Y., Uno Y., Akari H., Ishida T., Kimura A. Immunogenetics 60:727-735(2008) [PubMed: 18810425] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[4]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[5]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). Tissue: Umbilical cord blood.
[6]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Pancreas.
[7]	"Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6." Kawai T., Sato S., Ishii K.J., Coban C., Hemmi H., Yamamoto M., Terai K., Matsuda M., Inoue J., Uematsu S., Takeuchi O., Akira S. Nat. Immunol. 5:1061-1068(2004) [PubMed: 15361868] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH IRF7.
[8]	"Role of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signaling." Honda K., Yanai H., Mizutani T., Negishi H., Shimada N., Suzuki N., Ohba Y., Takaoka A., Yeh W.C., Taniguchi T. Proc. Natl. Acad. Sci. U.S.A. 101:15416-15421(2004) [PubMed: 15492225] [Abstract] Cited for: SUBCELLULAR LOCATION, INTERACTION WITH IRF7.
[9]	"IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST 2 and induces T helper type 2-associated cytokines." Schmitz J., Owyang A., Oldham E., Song Y., Murphy E., McClanahan T.K., Zurawski G., Moshrefi M., Qin J., Li X., Gorman D.M., Bazan J.F., Kastelein R.A. Immunity 23:479-490(2005) [PubMed: 16286016] [Abstract] Cited for: INTERACTION WITH IL1RL1.
[10]	"Etk/BMX, a Btk family tyrosine kinase, and Mal contribute to the cross-talk between MyD88 and FAK pathways." Semaan N., Alsaleh G., Gottenberg J.E., Wachsmann D., Sibilia J. J. Immunol. 180:3485-3491(2008) [PubMed: 18292575] [Abstract] Cited for: FUNCTION, INTERACTION WITH BMX.
[11]	"Modulation of TLR signaling by multiple MyD88-interacting partners including leucine-rich repeat Fli-I-interacting proteins." Dai P., Jeong S.Y., Yu Y., Leng T., Wu W., Xie L., Chen X. J. Immunol. 182:3450-3460(2009) [PubMed: 19265123] [Abstract] Cited for: INTERACTION WITH FLII; LRRFIP1 AND LRRFIP2.
[12]	"Structural basis for the multiple interactions of the MyD88 TIR domain in TLR4 signaling." Ohnishi H., Tochio H., Kato Z., Orii K.E., Li A., Kimura T., Hiroaki H., Kondo N., Shirakawa M. Proc. Natl. Acad. Sci. U.S.A. 106:10260-10265(2009) [PubMed: 19506249] [Abstract] Cited for: STRUCTURE BY NMR OF 148-296, FUNCTION, INTERACTION WITH TIRAP AND IRAK4, MUTAGENESIS OF ARG-196; ASP-197; ARG-217; LYS-282 AND ARG-288, CHARACTERIZATION OF VARIANT MYD88D CYS-196.
[13]	"Solution NMR structure of human myeloid differentiation primary response (MYD88)." Northeast structural genomics consortium (NESG) Submitted (FEB-2009) to the PDB data bank Cited for: STRUCTURE BY NMR OF 146-296.
[14]	"Pyogenic bacterial infections in humans with MyD88 deficiency." von Bernuth H., Picard C., Jin Z., Pankla R., Xiao H., Ku C.-L., Chrabieh M., Mustapha I.B., Ghandil P., Camcioglu Y., Vasconcelos J., Sirvent N., Guedes M., Vitor A.B., Herrero-Mata M.J., Arostegui J.I., Rodrigo C., Alsina L. , Ruiz-Ortiz E., Juan M., Fortuny C., Yaguee J., Anton J., Pascal M., Chang H.-H., Janniere L., Rose Y., Garty B.-Z., Chapel H., Issekutz A., Marodi L., Rodriguez-Gallego C., Banchereau J., Abel L., Li X., Chaussabel D., Puel A., Casanova J.-L. Science 321:691-696(2008) [PubMed: 18669862] [Abstract] Cited for: VARIANTS MYD88D PRO-93 AND CYS-196, CHARACTERIZATION OF VARIANTS MYD88D PRO-93 AND CYS-196.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U70451 mRNA. Translation: AAB49967.1.
U84408 mRNA. Translation: AAC50954.1.
AB446470 mRNA. Translation: BAG55247.1.
BT007376 mRNA. Translation: AAP36040.1.
AK296570 mRNA. Translation: BAG59190.1.
BC013589 mRNA. Translation: AAH13589.1.

IPI

IPI00878858.
IPI00925056.

RefSeq

NP_001166037.1. NM_001172566.1.
NP_001166039.1. NM_001172568.1.
NP_001166040.1. NM_001172569.1.
NP_002459.2. NM_002468.4.

UniGene

Hs.82116.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2JS7	NMR	-	A	146-296	[»]
2Z5V	NMR	-	A	148-296	[»]
3MOP	X-ray	3.40	A/B/C/D/E/F	20-117	[»]

ProteinModelPortal

Q99836.

SMR

Q99836. Positions 20-117, 146-296.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q99836. 30 interactions.

MINT

MINT-97233.

STRING

Q99836.

PTM databases

PhosphoSite

Q99836.

Polymorphism databases

DMDM

18202671.

Proteomic databases

PRIDE

Q99836.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000396334; ENSP00000379625; ENSG00000172936.
ENST00000415158; ENSP00000392152; ENSG00000172936.
ENST00000417037; ENSP00000401399; ENSG00000172936.
ENST00000424893; ENSP00000389979; ENSG00000172936.

GeneID

4615.

KEGG

hsa:4615.

UCSC

uc003chw.1. human.

Organism-specific databases

CTD

4615.

GeneCards

GC03P038155.

HGNC

HGNC:7562. MYD88.

HPA

CAB009104.

MIM

602170. gene.
612260. phenotype.

neXtProt

NX_Q99836.

Orphanet

183713. Pyogenic bacterial infections due to MyD88 deficiency.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG08701.

GeneTree

ENSGT00510000048324.

HOVERGEN

HBG052547.

InParanoid

Q99836.

OrthoDB

EOG4GXFNH.

PhylomeDB

Q99836.

Enzyme and pathway databases

Pathway_Interaction_DB

il1pathway. IL1-mediated signaling events.
p75ntrpathway. p75(NTR)-mediated signaling.

Reactome

REACT_111102. Signal Transduction.
REACT_6900. Immune System.

Gene expression databases

ArrayExpress

Q99836.

Bgee

Q99836.

CleanEx

HS_MYD88.

Genevestigator

Q99836.

GermOnline

ENSG00000172936. Homo sapiens.

Family and domain databases

InterPro

IPR000488. Death.
IPR011029. DEATH-like.
IPR017281. Myelin_different_resp_MyD88.
IPR000157. TIR_dom.
[Graphical view]

Gene3D

G3DSA:1.10.533.10. DEATH_like. 1 hit.

KO

K04729.

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

17764.

SOURCE

Search...

Entry information

Entry name

MYD88_HUMAN

Accession

Primary (citable) accession number: Q99836
Secondary accession number(s): B4DKH8, P78397, Q53XS7

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 18, 2001
Last sequence update:	May 1, 1997
Last modified:	January 25, 2012
This is version 118 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.