ID MYD88_HUMAN Reviewed; 296 AA.
AC Q99836; B4DKH8; B4DKU4; B4DQ60; B4DQ72; J3KPU4; J3KQ87; J3KQJ6; P78397;
AC Q53XS7;
DT 18-OCT-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1997, sequence version 1.
DT 24-JUL-2024, entry version 223.
DE RecName: Full=Myeloid differentiation primary response protein MyD88 {ECO:0000305};
GN Name=MYD88 {ECO:0000312|HGNC:HGNC:7562};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, AND VARIANT
RP CYS-98.
RC TISSUE=Dendritic cell;
RX PubMed=8957090;
RA Hardiman G., Rock F.L., Balasubramanian S., Kastelein R.A., Bazan J.F.;
RT "Molecular characterization and modular analysis of human MyD88.";
RL Oncogene 13:2467-2475(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION.
RC TISSUE=Epidermal carcinoma;
RX PubMed=9013863; DOI=10.1016/s0014-5793(96)01506-2;
RA Bonnert T.P., Garka K.E., Parnet P., Sonoda G., Testa J.R., Sims J.E.;
RT "The cloning and characterization of human MyD88: a member of an IL-1
RT receptor related family.";
RL FEBS Lett. 402:81-84(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=18810425; DOI=10.1007/s00251-008-0332-0;
RA Nakajima T., Ohtani H., Satta Y., Uno Y., Akari H., Ishida T., Kimura A.;
RT "Natural selection in the TLR-related genes in the course of primate
RT evolution.";
RL Immunogenetics 60:727-735(2008).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2; 3; 4 AND 5).
RC TISSUE=Umbilical cord blood;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J.,
RA Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P.,
RA Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A.,
RA Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G.,
RA Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W.,
RA Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M.,
RA Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P.,
RA Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H.,
RA Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J.,
RA Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W.,
RA Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B.,
RA Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O.,
RA Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X.,
RA Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R.,
RA Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND NUCLEOTIDE SEQUENCE
RP [MRNA] OF 190-224 (ISOFORM 6).
RC TISSUE=Pancreas;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [9]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH IRF7.
RX PubMed=15361868; DOI=10.1038/ni1118;
RA Kawai T., Sato S., Ishii K.J., Coban C., Hemmi H., Yamamoto M., Terai K.,
RA Matsuda M., Inoue J., Uematsu S., Takeuchi O., Akira S.;
RT "Interferon-alpha induction through Toll-like receptors involves a direct
RT interaction of IRF7 with MyD88 and TRAF6.";
RL Nat. Immunol. 5:1061-1068(2004).
RN [10]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH IRF7.
RX PubMed=15492225; DOI=10.1073/pnas.0406933101;
RA Honda K., Yanai H., Mizutani T., Negishi H., Shimada N., Suzuki N.,
RA Ohba Y., Takaoka A., Yeh W.C., Taniguchi T.;
RT "Role of a transductional-transcriptional processor complex involving MyD88
RT and IRF-7 in Toll-like receptor signaling.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:15416-15421(2004).
RN [11]
RP INTERACTION WITH IL1RL1.
RX PubMed=16286016; DOI=10.1016/j.immuni.2005.09.015;
RA Schmitz J., Owyang A., Oldham E., Song Y., Murphy E., McClanahan T.K.,
RA Zurawski G., Moshrefi M., Qin J., Li X., Gorman D.M., Bazan J.F.,
RA Kastelein R.A.;
RT "IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-
RT related protein ST 2 and induces T helper type 2-associated cytokines.";
RL Immunity 23:479-490(2005).
RN [12]
RP IDENTIFICATION IN COMPLEX WITH IRAK1; IRAK4; TRAF6 AND PELI1.
RX PubMed=16951688; DOI=10.1038/ni1383;
RA Choi K.C., Lee Y.S., Lim S., Choi H.K., Lee C.H., Lee E.K., Hong S.,
RA Kim I.H., Kim S.J., Park S.H.;
RT "Smad6 negatively regulates interleukin 1-receptor-Toll-like receptor
RT signaling through direct interaction with the adapter Pellino-1.";
RL Nat. Immunol. 7:1057-1065(2006).
RN [13]
RP INTERACTION WITH TIRAP.
RX PubMed=17322885; DOI=10.1038/ng1976;
RA Khor C.C., Chapman S.J., Vannberg F.O., Dunne A., Murphy C., Ling E.Y.,
RA Frodsham A.J., Walley A.J., Kyrieleis O., Khan A., Aucan C., Segal S.,
RA Moore C.E., Knox K., Campbell S.J., Lienhardt C., Scott A., Aaby P.,
RA Sow O.Y., Grignani R.T., Sillah J., Sirugo G., Peshu N., Williams T.N.,
RA Maitland K., Davies R.J.O., Kwiatkowski D.P., Day N.P., Yala D.,
RA Crook D.W., Marsh K., Berkley J.A., O'Neill L.A.J., Hill A.V.S.;
RT "A Mal functional variant is associated with protection against invasive
RT pneumococcal disease, bacteremia, malaria and tuberculosis.";
RL Nat. Genet. 39:523-528(2007).
RN [14]
RP FUNCTION, AND INTERACTION WITH BMX.
RX PubMed=18292575; DOI=10.4049/jimmunol.180.5.3485;
RA Semaan N., Alsaleh G., Gottenberg J.E., Wachsmann D., Sibilia J.;
RT "Etk/BMX, a Btk family tyrosine kinase, and Mal contribute to the cross-
RT talk between MyD88 and FAK pathways.";
RL J. Immunol. 180:3485-3491(2008).
RN [15]
RP INTERACTION WITH FLII; LRRFIP1 AND LRRFIP2.
RX PubMed=19265123; DOI=10.4049/jimmunol.0802260;
RA Dai P., Jeong S.Y., Yu Y., Leng T., Wu W., Xie L., Chen X.;
RT "Modulation of TLR signaling by multiple MyD88-interacting partners
RT including leucine-rich repeat Fli-I-interacting proteins.";
RL J. Immunol. 182:3450-3460(2009).
RN [16]
RP FUNCTION, AND INTERACTION WITH TLR5.
RX PubMed=20855887; DOI=10.1074/jbc.m110.158394;
RA Choi Y.J., Im E., Chung H.K., Pothoulakis C., Rhee S.H.;
RT "TRIF mediates Toll-like receptor 5-induced signaling in intestinal
RT epithelial cells.";
RL J. Biol. Chem. 285:37570-37578(2010).
RN [17]
RP INTERACTION WITH TIRAP.
RX PubMed=19948740; DOI=10.1074/jbc.m109.069385;
RA Wan T., Liu T., Zhang H., Tang S., Min W.;
RT "AIP1 functions as Arf6-GAP to negatively regulate TLR4 signaling.";
RL J. Biol. Chem. 285:3750-3757(2010).
RN [18]
RP INTERACTION WITH DHX9.
RX PubMed=20696886; DOI=10.1073/pnas.1006539107;
RA Kim T., Pazhoor S., Bao M., Zhang Z., Hanabuchi S., Facchinetti V.,
RA Bover L., Plumas J., Chaperot L., Qin J., Liu Y.J.;
RT "Aspartate-glutamate-alanine-histidine box motif (DEAH)/RNA helicase A
RT helicases sense microbial DNA in human plasmacytoid dendritic cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:15181-15186(2010).
RN [19]
RP INTERACTION WITH IRAK4, AND CHARACTERIZATION OF VARIANTS TYR-34; CYS-98 AND
RP ILE-178.
RX PubMed=20966070; DOI=10.1074/jbc.m110.159996;
RA George J., Motshwene P.G., Wang H., Kubarenko A.V., Rautanen A.,
RA Mills T.C., Hill A.V., Gay N.J., Weber A.N.;
RT "Two human MYD88 variants, S34Y and R98C, interfere with MyD88-IRAK4-
RT myddosome assembly.";
RL J. Biol. Chem. 286:1341-1353(2011).
RN [20]
RP INTERACTION WITH B.MELITENSIS TCPB (MICROBIAL INFECTION).
RX PubMed=22155231; DOI=10.1016/j.bbrc.2011.11.104;
RA Chaudhary A., Ganguly K., Cabantous S., Waldo G.S., Micheva-Viteva S.N.,
RA Nag K., Hlavacek W.S., Tung C.S.;
RT "The Brucella TIR-like protein TcpB interacts with the death domain of
RT MyD88.";
RL Biochem. Biophys. Res. Commun. 417:299-304(2012).
RN [21]
RP INTERACTION WITH IKBKE.
RX PubMed=23453969; DOI=10.1016/j.celrep.2013.01.031;
RA Zhou A.Y., Shen R.R., Kim E., Lock Y.J., Xu M., Chen Z.J., Hahn W.C.;
RT "IKKepsilon-mediated tumorigenesis requires K63-linked polyubiquitination
RT by a cIAP1/cIAP2/TRAF2 E3 ubiquitin ligase complex.";
RL Cell Rep. 3:724-733(2013).
RN [22]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-244, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [23]
RP FUNCTION, INTERACTION WITH IRAK4, CHARACTERIZATION OF VARIANTS TYR-34;
RP CYS-98 AND ILE-178, AND CHARACTERIZATION OF VARIANTS IMD68 GLU-52 DEL;
RP PRO-93 AND CYS-196.
RX PubMed=24316379; DOI=10.1016/j.molimm.2013.11.008;
RA Yamamoto T., Tsutsumi N., Tochio H., Ohnishi H., Kubota K., Kato Z.,
RA Shirakawa M., Kondo N.;
RT "Functional assessment of the mutational effects of human IRAK4 and MyD88
RT genes.";
RL Mol. Immunol. 58:66-76(2014).
RN [24]
RP INTERACTION WITH B.MELITENSIS PROTEIN TCPB (MICROBIAL INFECTION).
RX PubMed=24265315; DOI=10.1074/jbc.m113.523274;
RA Alaidarous M., Ve T., Casey L.W., Valkov E., Ericsson D.J., Ullah M.O.,
RA Schembri M.A., Mansell A., Sweet M.J., Kobe B.;
RT "Mechanism of bacterial interference with TLR4 signaling by Brucella
RT Toll/interleukin-1 receptor domain-containing protein TcpB.";
RL J. Biol. Chem. 289:654-668(2014).
RN [25]
RP INTERACTION WITH E.FAECALIS PROTEIN TCPF (MICROBIAL INFECTION).
RX PubMed=25369374; DOI=10.1371/journal.pone.0112010;
RA Zou J., Baghdayan A.S., Payne S.J., Shankar N.;
RT "A TIR domain protein from E. faecalis attenuates MyD88-mediated signaling
RT and NF-kappaB activation.";
RL PLoS ONE 9:E112010-E112010(2014).
RN [26]
RP INTERACTION WITH HUMAN METAPNEUMOVIRUS M2-2 (MICROBIAL INFECTION).
RX PubMed=24618691; DOI=10.1371/journal.pone.0091865;
RA Ren J., Liu G., Go J., Kolli D., Zhang G., Bao X.;
RT "Human metapneumovirus M2-2 protein inhibits innate immune response in
RT monocyte-derived dendritic cells.";
RL PLoS ONE 9:e91865-e91865(2014).
RN [27]
RP UBIQUITINATION BY HUMAN HERPESVIRUS 8 PROTEIN RTA/ORF50 (MICROBIAL
RP INFECTION).
RX PubMed=25320320; DOI=10.1128/jvi.02591-14;
RA Zhao Q., Liang D., Sun R., Jia B., Xia T., Xiao H., Lan K.;
RT "Kaposi's sarcoma-associated herpesvirus-encoded replication and
RT transcription activator impairs innate immunity via ubiquitin-mediated
RT degradation of myeloid differentiation factor 88.";
RL J. Virol. 89:415-427(2015).
RN [28]
RP INTERACTION WITH OTUD4, AND UBIQUITINATION.
RX PubMed=29395066; DOI=10.1016/j.molcel.2018.01.009;
RA Zhao Y., Mudge M.C., Soll J.M., Rodrigues R.B., Byrum A.K.,
RA Schwarzkopf E.A., Bradstreet T.R., Gygi S.P., Edelson B.T.,
RA Mosammaparast N.;
RT "OTUD4 Is a Phospho-Activated K63 Deubiquitinase that Regulates MyD88-
RT Dependent Signaling.";
RL Mol. Cell 69:505-516(2018).
RN [29]
RP FUNCTION.
RX PubMed=33718825; DOI=10.1016/j.isci.2021.102295;
RA Campbell G.R., To R.K., Hanna J., Spector S.A.;
RT "SARS-CoV-2, SARS-CoV-1, and HIV-1 derived ssRNA sequences activate the
RT NLRP3 inflammasome in human macrophages through a non-classical pathway.";
RL IScience 1:102295-102295(2021).
RN [30]
RP INTERACTION WITH TLR4.
RX PubMed=36232715; DOI=10.3390/ijms231911414;
RA Youn S.E., Jiang F., Won H.Y., Hong D.E., Kang T.H., Park Y.Y., Koh S.S.;
RT "PAUF Induces Migration of Human Pancreatic Cancer Cells Exclusively via
RT the TLR4/MyD88/NF-kappaB Signaling Pathway.";
RL Int. J. Mol. Sci. 23:0-0(2022).
RN [31]
RP FUNCTION, SUBCELLULAR LOCATION, AND DEUBIQUITINATION BY USP3.
RX PubMed=37971847; DOI=10.15252/embr.202357828;
RA Duan T., Feng Y., Du Y., Xing C., Chu J., Ou J., Liu X., Zhu M., Qian C.,
RA Yin B., Wang H.Y., Cui J., Wang R.F.;
RT "USP3 plays a critical role in the induction of innate immune tolerance.";
RL EMBO Rep. 24:e57828-e57828(2023).
RN [32]
RP STRUCTURE BY NMR OF 148-296, FUNCTION, INTERACTION WITH TIRAP AND IRAK4,
RP MUTAGENESIS OF ARG-196; ASP-197; ARG-217; LYS-282 AND ARG-288, AND
RP CHARACTERIZATION OF VARIANT IMD68 CYS-196.
RX PubMed=19506249; DOI=10.1073/pnas.0812956106;
RA Ohnishi H., Tochio H., Kato Z., Orii K.E., Li A., Kimura T., Hiroaki H.,
RA Kondo N., Shirakawa M.;
RT "Structural basis for the multiple interactions of the MyD88 TIR domain in
RT TLR4 signaling.";
RL Proc. Natl. Acad. Sci. U.S.A. 106:10260-10265(2009).
RN [33]
RP STRUCTURE BY NMR OF 146-296.
RG Northeast structural genomics consortium (NESG);
RT "Solution NMR structure of human myeloid differentiation primary response
RT (MYD88).";
RL Submitted (FEB-2009) to the PDB data bank.
RN [34] {ECO:0007744|PDB:4DOM, ECO:0007744|PDB:4EO7}
RP X-RAY CRYSTALLOGRAPHY (1.45 ANGSTROMS) OF 157-296, MUTAGENESIS OF ILE-179;
RP CYS-203 AND CYS-280, AND INTERACTION WITH E.COLI PROTEIN TCPC (MICROBIAL
RP INFECTION).
RX PubMed=23569230; DOI=10.1073/pnas.1215770110;
RA Snyder G.A., Cirl C., Jiang J., Chen K., Waldhuber A., Smith P.,
RA Roemmler F., Snyder N., Fresquez T., Duerr S., Tjandra N., Miethke T.,
RA Xiao T.S.;
RT "Molecular mechanisms for the subversion of MyD88 signaling by TcpC from
RT virulent uropathogenic Escherichia coli.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:6985-6990(2013).
RN [35]
RP VARIANTS IMD68 PRO-93 AND CYS-196, AND CHARACTERIZATION OF VARIANTS IMD68
RP PRO-93 AND CYS-196.
RX PubMed=18669862; DOI=10.1126/science.1158298;
RA von Bernuth H., Picard C., Jin Z., Pankla R., Xiao H., Ku C.-L.,
RA Chrabieh M., Mustapha I.B., Ghandil P., Camcioglu Y., Vasconcelos J.,
RA Sirvent N., Guedes M., Vitor A.B., Herrero-Mata M.J., Arostegui J.I.,
RA Rodrigo C., Alsina L., Ruiz-Ortiz E., Juan M., Fortuny C., Yaguee J.,
RA Anton J., Pascal M., Chang H.-H., Janniere L., Rose Y., Garty B.-Z.,
RA Chapel H., Issekutz A., Marodi L., Rodriguez-Gallego C., Banchereau J.,
RA Abel L., Li X., Chaussabel D., Puel A., Casanova J.-L.;
RT "Pyogenic bacterial infections in humans with MyD88 deficiency.";
RL Science 321:691-696(2008).
RN [36]
RP INVOLVEMENT IN IMD68, AND VARIANTS IMD68 GLU-52 DEL; PRO-93 AND CYS-196.
RX PubMed=21057262; DOI=10.1097/md.0b013e3181fd8ec3;
RA Picard C., von Bernuth H., Ghandil P., Chrabieh M., Levy O.,
RA Arkwright P.D., McDonald D., Geha R.S., Takada H., Krause J.C.,
RA Creech C.B., Ku C.L., Ehl S., Marodi L., Al-Muhsen S., Al-Hajjar S.,
RA Al-Ghonaium A., Day-Good N.K., Holland S.M., Gallin J.I., Chapel H.,
RA Speert D.P., Rodriguez-Gallego C., Colino E., Garty B.Z., Roifman C.,
RA Hara T., Yoshikawa H., Nonoyama S., Domachowske J., Issekutz A.C., Tang M.,
RA Smart J., Zitnik S.E., Hoarau C., Kumararatne D.S., Thrasher A.J.,
RA Davies E.G., Bethune C., Sirvent N., de Ricaud D., Camcioglu Y.,
RA Vasconcelos J., Guedes M., Vitor A.B., Rodrigo C., Almazan F., Mendez M.,
RA Arostegui J.I., Alsina L., Fortuny C., Reichenbach J., Verbsky J.W.,
RA Bossuyt X., Doffinger R., Abel L., Puel A., Casanova J.L.;
RT "Clinical features and outcome of patients with IRAK-4 and MyD88
RT deficiency.";
RL Medicine (Baltimore) 89:403-425(2010).
RN [37]
RP VARIANTS MET-39; GLY-136; ILE-136; PHE-204; ARG-205; CYS-206; THR-207;
RP ARG-209; THR-219; ASN-230 AND PRO-281, CHARACTERIZATION OF VARIANTS
RP ARG-209; THR-219; ASN-230 AND PRO-281, INTERACTION WITH IRAK4, VARIANT WM1
RP PRO-252, AND CHARACTERIZATION OF VARIANT WM1 PRO-252.
RX PubMed=21179087; DOI=10.1038/nature09671;
RA Ngo V.N., Young R.M., Schmitz R., Jhavar S., Xiao W., Lim K.H.,
RA Kohlhammer H., Xu W., Yang Y., Zhao H., Shaffer A.L., Romesser P.,
RA Wright G., Powell J., Rosenwald A., Muller-Hermelink H.K., Ott G.,
RA Gascoyne R.D., Connors J.M., Rimsza L.M., Campo E., Jaffe E.S., Delabie J.,
RA Smeland E.B., Fisher R.I., Braziel R.M., Tubbs R.R., Cook J.R.,
RA Weisenburger D.D., Chan W.C., Staudt L.M.;
RT "Oncogenically active MYD88 mutations in human lymphoma.";
RL Nature 470:115-119(2011).
RN [38]
RP VARIANT WM1 PRO-252.
RX PubMed=22931316; DOI=10.1056/nejmoa1200710;
RA Treon S.P., Xu L., Yang G., Zhou Y., Liu X., Cao Y., Sheehy P.,
RA Manning R.J., Patterson C.J., Tripsas C., Arcaini L., Pinkus G.S.,
RA Rodig S.J., Sohani A.R., Harris N.L., Laramie J.M., Skifter D.A.,
RA Lincoln S.E., Hunter Z.R.;
RT "MYD88 L265P somatic mutation in Waldenstrom's macroglobulinemia.";
RL N. Engl. J. Med. 367:826-833(2012).
RN [39]
RP VARIANT WM1 PRO-252.
RX PubMed=24366360; DOI=10.1182/blood-2013-09-525808;
RA Hunter Z.R., Xu L., Yang G., Zhou Y., Liu X., Cao Y., Manning R.J.,
RA Tripsas C., Patterson C.J., Sheehy P., Treon S.P.;
RT "The genomic landscape of Waldenstrom macroglobulinemia is characterized by
RT highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic
RT deletions associated with B-cell lymphomagenesis.";
RL Blood 123:1637-1646(2014).
CC -!- FUNCTION: Adapter protein involved in the Toll-like receptor and IL-1
CC receptor signaling pathway in the innate immune response
CC (PubMed:15361868, PubMed:18292575, PubMed:33718825, PubMed:37971847).
CC Acts via IRAK1, IRAK2, IRF7 and TRAF6, leading to NF-kappa-B
CC activation, cytokine secretion and the inflammatory response
CC (PubMed:15361868, PubMed:19506249, PubMed:24316379). Increases IL-8
CC transcription (PubMed:9013863). Involved in IL-18-mediated signaling
CC pathway. Activates IRF1 resulting in its rapid migration into the
CC nucleus to mediate an efficient induction of IFN-beta, NOS2/INOS, and
CC IL12A genes. Upon TLR8 activation by GU-rich single-stranded RNA (GU-
CC rich RNA) derived from viruses such as SARS-CoV-2, SARS-CoV and HIV-1,
CC induces IL1B release through NLRP3 inflammasome activation
CC (PubMed:33718825). MyD88-mediated signaling in intestinal epithelial
CC cells is crucial for maintenance of gut homeostasis and controls the
CC expression of the antimicrobial lectin REG3G in the small intestine (By
CC similarity). {ECO:0000250|UniProtKB:P22366,
CC ECO:0000269|PubMed:15361868, ECO:0000269|PubMed:18292575,
CC ECO:0000269|PubMed:19506249, ECO:0000269|PubMed:20855887,
CC ECO:0000269|PubMed:24316379, ECO:0000269|PubMed:33718825,
CC ECO:0000269|PubMed:37971847, ECO:0000269|PubMed:9013863}.
CC -!- SUBUNIT: Homodimer. Also forms heterodimers with TIRAP
CC (PubMed:17322885, PubMed:19506249, PubMed:19948740). Binds to TLR2,
CC TLR5, IRAK1, IRAK2 and IRAK4 via their respective TIR domains.
CC Interacts with IL18R1. Interacts with BMX, IL1RL1, IKBKE and IRF7.
CC Interacts with LRRFIP1 and LRRFIP2; this interaction positively
CC regulates Toll-like receptor (TLR) signaling in response to agonist.
CC Interacts with FLII. LRRFIP1 and LRRFIP2 compete with FLII for MYD88-
CC binding. Interacts with IRF1. Upon IL1B treatment, forms a complex with
CC PELI1, IRAK1, IRAK4 and TRAF6; this complex recruits MAP3K7/TAK1, TAB1
CC and TAB2 to mediate NF-kappa-B activation. Direct binding of SMAD6 to
CC PELI1 prevents the complex formation and hence negatively regulates
CC IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression.
CC May interact with PIK3AP1. Interacts (via TIR domain) with DHX9 (via
CC H2A and OB-fold regions); this interaction is direct (PubMed:20696886).
CC Interacts with OTUD4 deubiquitinase; the interaction is direct
CC (PubMed:29395066). Interacts with TLR4 (PubMed:36232715).
CC {ECO:0000269|PubMed:15361868, ECO:0000269|PubMed:15492225,
CC ECO:0000269|PubMed:16286016, ECO:0000269|PubMed:16951688,
CC ECO:0000269|PubMed:17322885, ECO:0000269|PubMed:18292575,
CC ECO:0000269|PubMed:19265123, ECO:0000269|PubMed:19506249,
CC ECO:0000269|PubMed:19948740, ECO:0000269|PubMed:20696886,
CC ECO:0000269|PubMed:20855887, ECO:0000269|PubMed:20966070,
CC ECO:0000269|PubMed:21179087, ECO:0000269|PubMed:23453969,
CC ECO:0000269|PubMed:24316379, ECO:0000269|PubMed:29395066,
CC ECO:0000269|PubMed:36232715}.
CC -!- SUBUNIT: (Microbial infection) In case of infection, interacts with
CC uropathogenic E.coli protein TcpC; suppressing Toll-like receptor
CC (TLR)-mediated cytokine production. {ECO:0000269|PubMed:23569230}.
CC -!- SUBUNIT: (Microbial infection) In case of infection, interacts with
CC uropathogenic E.faecalis protein TcpF; suppressing Toll-like receptor
CC (TLR)-mediated cytokine production. {ECO:0000269|PubMed:25369374}.
CC -!- SUBUNIT: (Microbial infection) In case of infection, interacts with
CC B.melitensis protein TcpB. {ECO:0000269|PubMed:22155231,
CC ECO:0000269|PubMed:24265315}.
CC -!- SUBUNIT: (Microbial infection) Interacts with human metapneumovirus
CC protein M2-2; this interaction prevents MYD88-mediated cytokine
CC secretion. {ECO:0000269|PubMed:24618691}.
CC -!- INTERACTION:
CC Q99836; Q8NF50: DOCK8; NbExp=3; IntAct=EBI-447677, EBI-2548605;
CC Q99836; Q13158: FADD; NbExp=3; IntAct=EBI-447677, EBI-494804;
CC Q99836; Q9UBN7: HDAC6; NbExp=6; IntAct=EBI-447677, EBI-301697;
CC Q99836; P51617: IRAK1; NbExp=3; IntAct=EBI-447677, EBI-358664;
CC Q99836; Q69FE3: IRAK4; NbExp=5; IntAct=EBI-447677, EBI-10249217;
CC Q99836; Q9NWZ3: IRAK4; NbExp=15; IntAct=EBI-447677, EBI-448378;
CC Q99836; Q99836: MYD88; NbExp=40; IntAct=EBI-447677, EBI-447677;
CC Q99836; Q96HA8: NTAQ1; NbExp=3; IntAct=EBI-447677, EBI-741158;
CC Q99836; P78317: RNF4; NbExp=3; IntAct=EBI-447677, EBI-2340927;
CC Q99836; Q6SZW1: SARM1; NbExp=5; IntAct=EBI-447677, EBI-11693532;
CC Q99836; Q8IUQ4: SIAH1; NbExp=3; IntAct=EBI-447677, EBI-747107;
CC Q99836; P84022: SMAD3; NbExp=3; IntAct=EBI-447677, EBI-347161;
CC Q99836; O43791: SPOP; NbExp=7; IntAct=EBI-447677, EBI-743549;
CC Q99836; Q6IQ16: SPOPL; NbExp=3; IntAct=EBI-447677, EBI-2822161;
CC Q99836; Q9UGK3: STAP2; NbExp=3; IntAct=EBI-447677, EBI-1553984;
CC Q99836; P58753: TIRAP; NbExp=8; IntAct=EBI-447677, EBI-528644;
CC Q99836; O60603: TLR2; NbExp=4; IntAct=EBI-447677, EBI-973722;
CC Q99836; O00206: TLR4; NbExp=4; IntAct=EBI-447677, EBI-528701;
CC Q99836; O14836: TNFRSF13B; NbExp=12; IntAct=EBI-447677, EBI-519160;
CC Q99836; P10599: TXN; NbExp=4; IntAct=EBI-447677, EBI-594644;
CC Q99836; Q93009: USP7; NbExp=3; IntAct=EBI-447677, EBI-302474;
CC Q99836; P13682: ZNF35; NbExp=3; IntAct=EBI-447677, EBI-11041653;
CC Q99836; Q8YF33: BMEI1694; Xeno; NbExp=4; IntAct=EBI-447677, EBI-11616155;
CC Q99836; PRO_0000278740 [Q03463]; Xeno; NbExp=3; IntAct=EBI-447677, EBI-8803426;
CC Q99836-1; Q99418: CYTH2; NbExp=3; IntAct=EBI-15855480, EBI-448974;
CC Q99836-1; Q9NWZ3: IRAK4; NbExp=9; IntAct=EBI-15855480, EBI-448378;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:15361868,
CC ECO:0000269|PubMed:15492225, ECO:0000269|PubMed:37971847}. Nucleus
CC {ECO:0000269|PubMed:21057262}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Name=1;
CC IsoId=Q99836-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q99836-2; Sequence=VSP_038887;
CC Name=3;
CC IsoId=Q99836-3; Sequence=VSP_043500;
CC Name=4;
CC IsoId=Q99836-4; Sequence=VSP_043498, VSP_043499, VSP_043500;
CC Name=5;
CC IsoId=Q99836-5; Sequence=VSP_053764;
CC Name=6;
CC IsoId=Q99836-6; Sequence=VSP_053765;
CC -!- TISSUE SPECIFICITY: Ubiquitous. {ECO:0000269|PubMed:8957090}.
CC -!- DOMAIN: The intermediate domain (ID) is required for the
CC phosphorylation and activation of IRAK. {ECO:0000250|UniProtKB:P22366}.
CC -!- PTM: Ubiquitinated; undergoes 'Lys-63'-linked polyubiquitination. OTUD4
CC specifically hydrolyzes 'Lys-63'-linked polyubiquitinated MYD88
CC (PubMed:29395066). Deubiquitinated by USP3 that cleaves 'Lys-63'-linked
CC ubiquitin chains leading to inhibition of MYD88-induced NF-kappa-B
CC signaling (PubMed:37971847). {ECO:0000269|PubMed:29395066,
CC ECO:0000269|PubMed:37971847}.
CC -!- PTM: (Microbial infection) Ubiquitinated by human herpesvirus 8 (KSHV)
CC protein RTA/ORF50, leading to proteasomal degradation ans suppression
CC of TLR4 signaling pathway. {ECO:0000269|PubMed:25320320}.
CC -!- DISEASE: Immunodeficiency 68 (IMD68) [MIM:612260]: An autosomal
CC recessive primary immunodeficiency characterized by life-threatening,
CC often recurrent, pyogenic bacterial infections, including invasive
CC pneumococcal disease, beginning in infancy or early childhood.
CC {ECO:0000269|PubMed:18669862, ECO:0000269|PubMed:19506249,
CC ECO:0000269|PubMed:21057262, ECO:0000269|PubMed:24316379}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Macroglobulinemia, Waldenstrom, 1 (WM1) [MIM:153600]: A
CC malignant B-cell neoplasm characterized by lymphoplasmacytic
CC infiltration of the bone marrow and hypersecretion of monoclonal
CC immunoglobulin M (IgM) protein. Clinical features are variable and
CC include anemia, thrombocytopenia, hepatosplenomegaly, and
CC lymphadenopathy. Many patients have asymptomatic or indolent disease.
CC {ECO:0000269|PubMed:21179087, ECO:0000269|PubMed:22931316,
CC ECO:0000269|PubMed:24366360}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Note=Defects in MYD88 are frequently found in many
CC hematological malignancies, such as activated B-cell type diffuse large
CC B-cell lymphoma (ABC-DLBCL), cutaneous diffuse large B cell lymphoma
CC (CBCL) and primary central nervous system lymphoma (PCNSL).
CC {ECO:0000269|PubMed:21179087, ECO:0000269|PubMed:22931316}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAG60822.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=BAG60834.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=EAW64521.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
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DR EMBL; U70451; AAB49967.1; -; mRNA.
DR EMBL; U84408; AAC50954.1; -; mRNA.
DR EMBL; AB446470; BAG55247.1; -; mRNA.
DR EMBL; BT007376; AAP36040.1; -; mRNA.
DR EMBL; AK296570; BAG59190.1; -; mRNA.
DR EMBL; AK296716; BAG59306.1; -; mRNA.
DR EMBL; AK298650; BAG60822.1; ALT_INIT; mRNA.
DR EMBL; AK298666; BAG60834.1; ALT_INIT; mRNA.
DR EMBL; AP006309; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471055; EAW64521.1; ALT_SEQ; Genomic_DNA.
DR EMBL; BC013589; AAH13589.1; -; mRNA.
DR EMBL; BI524129; -; NOT_ANNOTATED_CDS; mRNA.
DR CCDS; CCDS2674.3; -. [Q99836-1]
DR CCDS; CCDS54565.2; -. [Q99836-6]
DR CCDS; CCDS54566.2; -. [Q99836-3]
DR CCDS; CCDS54567.2; -. [Q99836-2]
DR CCDS; CCDS54568.2; -. [Q99836-4]
DR RefSeq; NP_001166037.1; NM_001172566.1. [Q99836-4]
DR RefSeq; NP_001166039.1; NM_001172568.1. [Q99836-2]
DR RefSeq; NP_001166040.1; NM_001172569.1. [Q99836-3]
DR RefSeq; NP_002459.2; NM_002468.4. [Q99836-1]
DR PDB; 2JS7; NMR; -; A=146-296.
DR PDB; 2Z5V; NMR; -; A=148-296.
DR PDB; 3MOP; X-ray; 3.40 A; A/B/C/D/E/F=20-117.
DR PDB; 4DOM; X-ray; 1.80 A; A=157-296.
DR PDB; 4EO7; X-ray; 1.45 A; A=157-296.
DR PDB; 6I3N; EM; 3.10 A; A/B/C/D/E/F/G/H/I/J/K/L/M=1-151.
DR PDB; 7BEQ; EM; 3.00 A; A=154-296.
DR PDB; 7BER; X-ray; 2.30 A; A=154-296.
DR PDB; 7L6W; X-ray; 2.30 A; A=159-296.
DR PDBsum; 2JS7; -.
DR PDBsum; 2Z5V; -.
DR PDBsum; 3MOP; -.
DR PDBsum; 4DOM; -.
DR PDBsum; 4EO7; -.
DR PDBsum; 6I3N; -.
DR PDBsum; 7BEQ; -.
DR PDBsum; 7BER; -.
DR PDBsum; 7L6W; -.
DR AlphaFoldDB; Q99836; -.
DR EMDB; EMD-4405; -.
DR SMR; Q99836; -.
DR BioGRID; 110700; 84.
DR DIP; DIP-31349N; -.
DR IntAct; Q99836; 46.
DR MINT; Q99836; -.
DR STRING; 9606.ENSP00000498321; -.
DR BindingDB; Q99836; -.
DR ChEMBL; CHEMBL5919; -.
DR GlyGen; Q99836; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q99836; -.
DR PhosphoSitePlus; Q99836; -.
DR SwissPalm; Q99836; -.
DR BioMuta; MYD88; -.
DR DMDM; 18202671; -.
DR jPOST; Q99836; -.
DR MassIVE; Q99836; -.
DR PaxDb; 9606-ENSP00000401399; -.
DR PeptideAtlas; Q99836; -.
DR ProteomicsDB; 78500; -. [Q99836-1]
DR ProteomicsDB; 78501; -. [Q99836-2]
DR ProteomicsDB; 78502; -. [Q99836-3]
DR ProteomicsDB; 78503; -. [Q99836-4]
DR Pumba; Q99836; -.
DR TopDownProteomics; Q99836-4; -. [Q99836-4]
DR Antibodypedia; 3965; 1005 antibodies from 51 providers.
DR DNASU; 4615; -.
DR Ensembl; ENST00000417037.8; ENSP00000401399.4; ENSG00000172936.18. [Q99836-2]
DR Ensembl; ENST00000421516.3; ENSP00000391753.3; ENSG00000172936.18. [Q99836-6]
DR Ensembl; ENST00000650112.2; ENSP00000497991.2; ENSG00000172936.18. [Q99836-4]
DR Ensembl; ENST00000650905.2; ENSP00000498360.2; ENSG00000172936.18. [Q99836-1]
DR Ensembl; ENST00000651800.2; ENSP00000499012.2; ENSG00000172936.18. [Q99836-3]
DR GeneID; 4615; -.
DR KEGG; hsa:4615; -.
DR MANE-Select; ENST00000650905.2; ENSP00000498360.2; NM_002468.5; NP_002459.3.
DR UCSC; uc011ayj.3; human. [Q99836-1]
DR AGR; HGNC:7562; -.
DR CTD; 4615; -.
DR DisGeNET; 4615; -.
DR GeneCards; MYD88; -.
DR HGNC; HGNC:7562; MYD88.
DR HPA; ENSG00000172936; Low tissue specificity.
DR MalaCards; MYD88; -.
DR MIM; 153600; phenotype.
DR MIM; 602170; gene.
DR MIM; 612260; phenotype.
DR neXtProt; NX_Q99836; -.
DR OpenTargets; ENSG00000172936; -.
DR Orphanet; 183713; Bacterial susceptibility due to TLR signaling pathway deficiency.
DR Orphanet; 33226; Waldenstroem macroglobulinemia.
DR PharmGKB; PA31361; -.
DR VEuPathDB; HostDB:ENSG00000172936; -.
DR eggNOG; ENOG502QWKI; Eukaryota.
DR GeneTree; ENSGT00510000048324; -.
DR HOGENOM; CLU_116540_0_0_1; -.
DR InParanoid; Q99836; -.
DR OMA; SNECDFQ; -.
DR OrthoDB; 2964088at2759; -.
DR PhylomeDB; Q99836; -.
DR TreeFam; TF326264; -.
DR PathwayCommons; Q99836; -.
DR Reactome; R-HSA-1236974; ER-Phagosome pathway.
DR Reactome; R-HSA-1257604; PIP3 activates AKT signaling.
DR Reactome; R-HSA-166058; MyD88:MAL(TIRAP) cascade initiated on plasma membrane.
DR Reactome; R-HSA-1810476; RIP-mediated NFkB activation via ZBP1.
DR Reactome; R-HSA-209543; p75NTR recruits signalling complexes.
DR Reactome; R-HSA-3134963; DEx/H-box helicases activate type I IFN and inflammatory cytokines production.
DR Reactome; R-HSA-5602498; MyD88 deficiency (TLR2/4).
DR Reactome; R-HSA-5602680; MyD88 deficiency (TLR5).
DR Reactome; R-HSA-5603037; IRAK4 deficiency (TLR5).
DR Reactome; R-HSA-5603041; IRAK4 deficiency (TLR2/4).
DR Reactome; R-HSA-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
DR Reactome; R-HSA-9020702; Interleukin-1 signaling.
DR Reactome; R-HSA-975110; TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling.
DR Reactome; R-HSA-975138; TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation.
DR Reactome; R-HSA-975155; MyD88 dependent cascade initiated on endosome.
DR Reactome; R-HSA-975871; MyD88 cascade initiated on plasma membrane.
DR SignaLink; Q99836; -.
DR SIGNOR; Q99836; -.
DR BioGRID-ORCS; 4615; 26 hits in 1167 CRISPR screens.
DR ChiTaRS; MYD88; human.
DR EvolutionaryTrace; Q99836; -.
DR GeneWiki; MYD88; -.
DR GenomeRNAi; 4615; -.
DR Pharos; Q99836; Tbio.
DR PRO; PR:Q99836; -.
DR Proteomes; UP000005640; Chromosome 3.
DR RNAct; Q99836; Protein.
DR Bgee; ENSG00000172936; Expressed in leukocyte and 200 other cell types or tissues.
DR ExpressionAtlas; Q99836; baseline and differential.
DR GO; GO:0009986; C:cell surface; IDA:UniProt.
DR GO; GO:0005737; C:cytoplasm; IDA:AgBase.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0010008; C:endosome membrane; TAS:Reactome.
DR GO; GO:0031234; C:extrinsic component of cytoplasmic side of plasma membrane; IDA:UniProt.
DR GO; GO:0019897; C:extrinsic component of plasma membrane; IDA:UniProt.
DR GO; GO:0005634; C:nucleus; IDA:AgBase.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProt.
DR GO; GO:0032991; C:protein-containing complex; IEA:Ensembl.
DR GO; GO:0140674; F:ATP-dependent histone chaperone activity; IEA:Ensembl.
DR GO; GO:0005123; F:death receptor binding; TAS:ProtInc.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0005149; F:interleukin-1 receptor binding; IEA:Ensembl.
DR GO; GO:0060090; F:molecular adaptor activity; IDA:UniProt.
DR GO; GO:0035591; F:signaling adaptor activity; IDA:UniProt.
DR GO; GO:0070976; F:TIR domain binding; IPI:BHF-UCL.
DR GO; GO:0005121; F:Toll binding; IEA:Ensembl.
DR GO; GO:0035325; F:Toll-like receptor binding; IBA:GO_Central.
DR GO; GO:0070935; P:3'-UTR-mediated mRNA stabilization; IDA:BHF-UCL.
DR GO; GO:0006915; P:apoptotic process; IMP:AgBase.
DR GO; GO:0007166; P:cell surface receptor signaling pathway; TAS:ProtInc.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; ISS:ARUK-UCL.
DR GO; GO:0071260; P:cellular response to mechanical stimulus; IEP:UniProtKB.
DR GO; GO:0140052; P:cellular response to oxidised low-density lipoprotein particle stimulus; ISS:ARUK-UCL.
DR GO; GO:0042742; P:defense response to bacterium; IMP:BHF-UCL.
DR GO; GO:0050830; P:defense response to Gram-positive bacterium; ISS:UniProtKB.
DR GO; GO:0042832; P:defense response to protozoan; ISS:ARUK-UCL.
DR GO; GO:0051607; P:defense response to virus; IDA:UniProtKB.
DR GO; GO:0090557; P:establishment of endothelial intestinal barrier; IEA:Ensembl.
DR GO; GO:0010467; P:gene expression; IEA:Ensembl.
DR GO; GO:0016064; P:immunoglobulin mediated immune response; IEA:Ensembl.
DR GO; GO:0009682; P:induced systemic resistance; IEA:Ensembl.
DR GO; GO:0045087; P:innate immune response; IBA:GO_Central.
DR GO; GO:0070498; P:interleukin-1-mediated signaling pathway; IDA:UniProt.
DR GO; GO:0038172; P:interleukin-33-mediated signaling pathway; IDA:UniProt.
DR GO; GO:0007254; P:JNK cascade; IEA:Ensembl.
DR GO; GO:0002269; P:leukocyte activation involved in inflammatory response; IEA:Ensembl.
DR GO; GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0014004; P:microglia differentiation; IEA:Ensembl.
DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0002283; P:neutrophil activation involved in immune response; IEA:Ensembl.
DR GO; GO:0070944; P:neutrophil-mediated killing of bacterium; IEA:Ensembl.
DR GO; GO:0006909; P:phagocytosis; IMP:UniProtKB.
DR GO; GO:0043123; P:positive regulation of canonical NF-kappaB signal transduction; IEP:UniProtKB.
DR GO; GO:0032722; P:positive regulation of chemokine production; IEA:Ensembl.
DR GO; GO:1900017; P:positive regulation of cytokine production involved in inflammatory response; IMP:BHF-UCL.
DR GO; GO:0010628; P:positive regulation of gene expression; ISS:ARUK-UCL.
DR GO; GO:0032731; P:positive regulation of interleukin-1 beta production; IDA:UniProtKB.
DR GO; GO:0032740; P:positive regulation of interleukin-17 production; ISS:BHF-UCL.
DR GO; GO:0032747; P:positive regulation of interleukin-23 production; ISS:BHF-UCL.
DR GO; GO:0032755; P:positive regulation of interleukin-6 production; ISS:BHF-UCL.
DR GO; GO:0032757; P:positive regulation of interleukin-8 production; IMP:BHF-UCL.
DR GO; GO:0046330; P:positive regulation of JNK cascade; IEA:Ensembl.
DR GO; GO:0050671; P:positive regulation of lymphocyte proliferation; IEA:Ensembl.
DR GO; GO:0060907; P:positive regulation of macrophage cytokine production; IEA:Ensembl.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IMP:AgBase.
DR GO; GO:1900227; P:positive regulation of NLRP3 inflammasome complex assembly; IMP:UniProtKB.
DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IEA:Ensembl.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IEA:Ensembl.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IEA:Ensembl.
DR GO; GO:0032481; P:positive regulation of type I interferon production; IMP:BHF-UCL.
DR GO; GO:2000338; P:regulation of chemokine (C-X-C motif) ligand 1 production; IEA:Ensembl.
DR GO; GO:2000341; P:regulation of chemokine (C-X-C motif) ligand 2 production; IEA:Ensembl.
DR GO; GO:0050727; P:regulation of inflammatory response; ISS:BHF-UCL.
DR GO; GO:1902622; P:regulation of neutrophil migration; IEA:Ensembl.
DR GO; GO:0014075; P:response to amine; IEA:Ensembl.
DR GO; GO:0043200; P:response to amino acid; IEA:Ensembl.
DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl.
DR GO; GO:0070555; P:response to interleukin-1; IMP:BHF-UCL.
DR GO; GO:0002238; P:response to molecule of fungal origin; IEA:Ensembl.
DR GO; GO:0014070; P:response to organic cyclic compound; IEA:Ensembl.
DR GO; GO:0032494; P:response to peptidoglycan; IEA:Ensembl.
DR GO; GO:0007165; P:signal transduction; NAS:ProtInc.
DR GO; GO:0043588; P:skin development; IEA:Ensembl.
DR GO; GO:0008063; P:Toll signaling pathway; IBA:GO_Central.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; IDA:UniProt.
DR GO; GO:0034158; P:toll-like receptor 8 signaling pathway; IDA:UniProtKB.
DR GO; GO:0060337; P:type I interferon-mediated signaling pathway; IMP:BHF-UCL.
DR CDD; cd08312; Death_MyD88; 1.
DR Gene3D; 1.10.533.10; Death Domain, Fas; 1.
DR Gene3D; 3.40.50.10140; Toll/interleukin-1 receptor homology (TIR) domain; 1.
DR InterPro; IPR011029; DEATH-like_dom_sf.
DR InterPro; IPR000488; Death_domain.
DR InterPro; IPR034249; MyD88_Death.
DR InterPro; IPR017281; Myelin_different_resp_MyD88.
DR InterPro; IPR000157; TIR_dom.
DR InterPro; IPR035897; Toll_tir_struct_dom_sf.
DR PANTHER; PTHR15079; MYD88; 1.
DR PANTHER; PTHR15079:SF3; MYELOID DIFFERENTIATION PRIMARY RESPONSE PROTEIN MYD88; 1.
DR Pfam; PF00531; Death; 1.
DR Pfam; PF13676; TIR_2; 1.
DR PIRSF; PIRSF037756; MyD88; 1.
DR SMART; SM00005; DEATH; 1.
DR SMART; SM00255; TIR; 1.
DR SUPFAM; SSF47986; DEATH domain; 1.
DR SUPFAM; SSF52200; Toll/Interleukin receptor TIR domain; 1.
DR PROSITE; PS50017; DEATH_DOMAIN; 1.
DR PROSITE; PS50104; TIR; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Antiviral defense; Cytoplasm;
KW Disease variant; Immunity; Inflammatory response; Innate immunity; Nucleus;
KW Phosphoprotein; Reference proteome; Ubl conjugation.
FT CHAIN 1..296
FT /note="Myeloid differentiation primary response protein
FT MyD88"
FT /id="PRO_0000096666"
FT DOMAIN 54..109
FT /note="Death"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00064"
FT DOMAIN 159..293
FT /note="TIR"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00204"
FT REGION 110..155
FT /note="Intermediate domain"
FT /evidence="ECO:0000250"
FT MOD_RES 244
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT VAR_SEQ 1..22
FT /note="MAAGGPGAGSAAPVSSTSSLPL -> M (in isoform 5)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_053764"
FT VAR_SEQ 110..154
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_038887"
FT VAR_SEQ 110
FT /note="E -> G (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_043498"
FT VAR_SEQ 111..155
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_043499"
FT VAR_SEQ 156..296
FT /note="HMPERFDAFICYCPSDIQFVQEMIRQLEQTNYRLKLCVSDRDVLPGTCVWSI
FT ASELIEKRCRRMVVVVSDDYLQSKECDFQTKFALSLSPGAHQKRLIPIKYKAMKKEFPS
FT ILRFITVCDYTNPCTKSWFWTRLAKALSLP -> AAGWWWLSLMITCRARNVTSRPNLH
FT SASLQVPIRSD (in isoform 3 and isoform 4)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_043500"
FT VAR_SEQ 215
FT /note="R -> RLARRPRGG (in isoform 6)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_053765"
FT VARIANT 34
FT /note="S -> Y (rare variant; uncertain significance; loss
FT of NF-kappa-B complex activation; loss of interaction with
FT IRAK4; reduces homooligomerization; dbSNP:rs1319438)"
FT /evidence="ECO:0000269|PubMed:20966070,
FT ECO:0000269|PubMed:24316379"
FT /id="VAR_072893"
FT VARIANT 39
FT /note="V -> M (found in hematological malignancies;
FT uncertain significance; somatic mutation;
FT dbSNP:rs770387646)"
FT /evidence="ECO:0000269|PubMed:21179087"
FT /id="VAR_073252"
FT VARIANT 52
FT /note="Missing (in IMD68; loss of NF-kappa-B complex
FT activation)"
FT /evidence="ECO:0000269|PubMed:21057262,
FT ECO:0000269|PubMed:24316379"
FT /id="VAR_072894"
FT VARIANT 93
FT /note="L -> P (in IMD68; results in a loss of function;
FT loss of NF-kappa-B complex activation; dbSNP:rs137853065)"
FT /evidence="ECO:0000269|PubMed:18669862,
FT ECO:0000269|PubMed:21057262, ECO:0000269|PubMed:24316379"
FT /id="VAR_047953"
FT VARIANT 98
FT /note="R -> C (found in hematological malignancies;
FT uncertain significance; somatic mutation; loss of NF-kappa-
FT B complex activation; loss of interaction with IRAK4;
FT reduces homooligomerization; dbSNP:rs199396)"
FT /evidence="ECO:0000269|PubMed:20966070,
FT ECO:0000269|PubMed:24316379, ECO:0000269|PubMed:8957090"
FT /id="VAR_072895"
FT VARIANT 136
FT /note="S -> G (found in hematological malignancies;
FT uncertain significance; somatic mutation)"
FT /evidence="ECO:0000269|PubMed:21179087"
FT /id="VAR_073253"
FT VARIANT 136
FT /note="S -> I (found in hematological malignancies;
FT uncertain significance; somatic mutation)"
FT /evidence="ECO:0000269|PubMed:21179087"
FT /id="VAR_073254"
FT VARIANT 178
FT /note="M -> I (found in hematological malignancies;
FT uncertain significance; somatic mutation; no effect on NF-
FT kappaB complex activation; dbSNP:rs41285117)"
FT /evidence="ECO:0000269|PubMed:20966070,
FT ECO:0000269|PubMed:24316379"
FT /id="VAR_072896"
FT VARIANT 196
FT /note="R -> C (in IMD68; results in a loss of function;
FT decreases NF-kappa-B complex activation;
FT dbSNP:rs137853064)"
FT /evidence="ECO:0000269|PubMed:18669862,
FT ECO:0000269|PubMed:19506249, ECO:0000269|PubMed:21057262,
FT ECO:0000269|PubMed:24316379"
FT /id="VAR_047954"
FT VARIANT 204
FT /note="V -> F (found in hematological malignancies;
FT uncertain significance; somatic mutation;
FT dbSNP:rs776995408)"
FT /evidence="ECO:0000269|PubMed:21179087"
FT /id="VAR_073255"
FT VARIANT 205
FT /note="W -> R (found in hematological malignancies;
FT uncertain significance; somatic mutation)"
FT /evidence="ECO:0000269|PubMed:21179087"
FT /id="VAR_073256"
FT VARIANT 206
FT /note="S -> C (found in hematological malignancies;
FT uncertain significance; somatic mutation)"
FT /evidence="ECO:0000269|PubMed:21179087"
FT /id="VAR_073257"
FT VARIANT 207
FT /note="I -> T (found in hematological malignancies;
FT uncertain significance; somatic mutation)"
FT /evidence="ECO:0000269|PubMed:21179087"
FT /id="VAR_073258"
FT VARIANT 209
FT /note="S -> R (found in hematological malignancies;
FT uncertain significance; somatic mutation; constitutively
FT activates NF-kappaB complex activation)"
FT /evidence="ECO:0000269|PubMed:21179087"
FT /id="VAR_073259"
FT VARIANT 219
FT /note="M -> T (found in hematological malignancies;
FT uncertain significance; somatic mutation; constitutively
FT activates NF-kappaB complex activation)"
FT /evidence="ECO:0000269|PubMed:21179087"
FT /id="VAR_073260"
FT VARIANT 230
FT /note="S -> N (found in hematological malignancies;
FT uncertain significance; somatic mutation; constitutively
FT activates NF-kappaB complex activation;
FT dbSNP:rs1353791431)"
FT /evidence="ECO:0000269|PubMed:21179087"
FT /id="VAR_073261"
FT VARIANT 252
FT /note="L -> P (in WM1; uncertain significance; somatic
FT mutation; constitutively activates NF-kappaB complex
FT activation; gain-of-function mutation; does not affect
FT interaction with IRAK4; dbSNP:rs387907272)"
FT /evidence="ECO:0000269|PubMed:21179087,
FT ECO:0000269|PubMed:22931316, ECO:0000269|PubMed:24366360"
FT /id="VAR_073262"
FT VARIANT 281
FT /note="T -> P (found in hematological malignancies;
FT uncertain significance; somatic mutation; no effect on NF-
FT kappaB complex activation)"
FT /evidence="ECO:0000269|PubMed:21179087"
FT /id="VAR_073263"
FT MUTAGEN 179
FT /note="I->N: In Pococurante (Poc); abolished MYD88-
FT dependent sensing of most Toll-like receptor (TLR)
FT ligands."
FT /evidence="ECO:0000269|PubMed:23569230"
FT MUTAGEN 196
FT /note="R->A: Reduced interaction with TIRAP, and strongly
FT reduced activity. Strongly reduced interaction with TIRAP;
FT when associated with A-288."
FT /evidence="ECO:0000269|PubMed:19506249"
FT MUTAGEN 197
FT /note="D->A: Slightly reduced activity."
FT /evidence="ECO:0000269|PubMed:19506249"
FT MUTAGEN 203
FT /note="C->S: Abolished interaction with E.coli TcpC without
FT affecting ability to promote Toll-like receptor (TLR)-
FT mediated cytokine production; when associated with S-280."
FT /evidence="ECO:0000269|PubMed:23569230"
FT MUTAGEN 217
FT /note="R->A: Strongly reduced activity."
FT /evidence="ECO:0000269|PubMed:19506249"
FT MUTAGEN 280
FT /note="C->S: Abolished interaction with E.coli TcpC without
FT affecting ability to promote Toll-like receptor (TLR)-
FT mediated cytokine production; when associated with S-203."
FT /evidence="ECO:0000269|PubMed:23569230"
FT MUTAGEN 282
FT /note="K->A: Slightly reduced activity."
FT /evidence="ECO:0000269|PubMed:19506249"
FT MUTAGEN 288
FT /note="R->A: Slightly reduced activity, and reduced
FT interaction with TIRAP. Strongly reduced interaction with
FT TIRAP; when associated with A-196."
FT /evidence="ECO:0000269|PubMed:19506249"
FT CONFLICT 190
FT /note="K -> T (in Ref. 8; BI524129)"
FT /evidence="ECO:0000305"
FT CONFLICT 223..224
FT /note="VS -> WL (in Ref. 8; BI524129)"
FT /evidence="ECO:0000305"
FT HELIX 22..24
FT /evidence="ECO:0007829|PDB:6I3N"
FT HELIX 27..37
FT /evidence="ECO:0007829|PDB:6I3N"
FT STRAND 42..44
FT /evidence="ECO:0007829|PDB:6I3N"
FT HELIX 47..53
FT /evidence="ECO:0007829|PDB:6I3N"
FT HELIX 58..64
FT /evidence="ECO:0007829|PDB:6I3N"
FT STRAND 66..69
FT /evidence="ECO:0007829|PDB:3MOP"
FT HELIX 70..77
FT /evidence="ECO:0007829|PDB:6I3N"
FT STRAND 79..81
FT /evidence="ECO:0007829|PDB:6I3N"
FT HELIX 86..95
FT /evidence="ECO:0007829|PDB:6I3N"
FT HELIX 100..104
FT /evidence="ECO:0007829|PDB:6I3N"
FT HELIX 106..120
FT /evidence="ECO:0007829|PDB:6I3N"
FT STRAND 159..166
FT /evidence="ECO:0007829|PDB:4EO7"
FT HELIX 169..171
FT /evidence="ECO:0007829|PDB:4EO7"
FT HELIX 172..183
FT /evidence="ECO:0007829|PDB:4EO7"
FT STRAND 185..187
FT /evidence="ECO:0007829|PDB:4EO7"
FT STRAND 191..194
FT /evidence="ECO:0007829|PDB:4EO7"
FT HELIX 196..198
FT /evidence="ECO:0007829|PDB:4EO7"
FT HELIX 209..211
FT /evidence="ECO:0007829|PDB:4EO7"
FT HELIX 212..215
FT /evidence="ECO:0007829|PDB:4EO7"
FT STRAND 216..223
FT /evidence="ECO:0007829|PDB:4EO7"
FT HELIX 227..229
FT /evidence="ECO:0007829|PDB:4EO7"
FT HELIX 231..242
FT /evidence="ECO:0007829|PDB:4EO7"
FT HELIX 247..251
FT /evidence="ECO:0007829|PDB:4EO7"
FT STRAND 252..256
FT /evidence="ECO:0007829|PDB:4EO7"
FT HELIX 266..268
FT /evidence="ECO:0007829|PDB:4EO7"
FT STRAND 269..271
FT /evidence="ECO:0007829|PDB:4DOM"
FT STRAND 274..277
FT /evidence="ECO:0007829|PDB:7BER"
FT HELIX 279..281
FT /evidence="ECO:0007829|PDB:4EO7"
FT HELIX 282..284
FT /evidence="ECO:0007829|PDB:7BER"
FT HELIX 285..294
FT /evidence="ECO:0007829|PDB:4EO7"
SQ SEQUENCE 296 AA; 33233 MW; CEAE3F6B99524333 CRC64;
MAAGGPGAGS AAPVSSTSSL PLAALNMRVR RRLSLFLNVR TQVAADWTAL AEEMDFEYLE
IRQLETQADP TGRLLDAWQG RPGASVGRLL ELLTKLGRDD VLLELGPSIE EDCQKYILKQ
QQEEAEKPLQ VAAVDSSVPR TAELAGITTL DDPLGHMPER FDAFICYCPS DIQFVQEMIR
QLEQTNYRLK LCVSDRDVLP GTCVWSIASE LIEKRCRRMV VVVSDDYLQS KECDFQTKFA
LSLSPGAHQK RLIPIKYKAM KKEFPSILRF ITVCDYTNPC TKSWFWTRLA KALSLP
//