3mop

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{{STRUCTURE_3mop| PDB=3mop | SCENE= }}
 
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===The ternary Death Domain complex of MyD88, IRAK4, and IRAK2===
 
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{{ABSTRACT_PUBMED_20485341}}
 
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==Disease==
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==The ternary Death Domain complex of MyD88, IRAK4, and IRAK2==
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[[http://www.uniprot.org/uniprot/MYD88_HUMAN MYD88_HUMAN]] Defects in MYD88 are the cause of MYD88 deficiency (MYD88D) [MIM:[http://omim.org/entry/612260 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>PMID:19506249</ref><ref>PMID:18669862</ref> [[http://www.uniprot.org/uniprot/IRAK4_HUMAN IRAK4_HUMAN]] Defects in IRAK4 are the cause of recurrent isolated invasive pneumococcal disease type 1 (IPD1) [MIM:[http://omim.org/entry/610799 610799]]. Recurrent invasive pneumococcal disease (IPD) is defined as two episodes of IPD occurring at least 1 month apart, whether caused by the same or different serotypes or strains. Recurrent IPD occurs in at least 2% of patients in most series, making IPD the most important known risk factor for subsequent IPD.<ref>PMID:16950813</ref> Defects in IRAK4 are the cause of IRAK4 deficiency (IRAK4D) [MIM:[http://omim.org/entry/607676 607676]]. IRAK4 deficiency causes extracellular pyogenic bacterial and fungal infections in otherwise healthy children.<ref>PMID:12925671</ref><ref>PMID:12637671</ref>
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<StructureSection load='3mop' size='340' side='right'caption='[[3mop]], [[Resolution|resolution]] 3.40&Aring;' scene=''>
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== Structural highlights ==
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==Function==
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<table><tr><td colspan='2'>[[3mop]] is a 14 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3MOP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3MOP FirstGlance]. <br>
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[[http://www.uniprot.org/uniprot/MYD88_HUMAN MYD88_HUMAN]] 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. Activates IRF1 resulting in its rapid migration into the nucleus to mediate an efficient induction of IFN-beta, NOS2/INOS, and IL12A genes (By similarity).<ref>PMID:9013863</ref><ref>PMID:15361868</ref><ref>PMID:18292575</ref><ref>PMID:19506249</ref> [[http://www.uniprot.org/uniprot/IRAK2_HUMAN IRAK2_HUMAN]] Binds to the IL-1 type I receptor following IL-1 engagement, triggering intracellular signaling cascades leading to transcriptional up-regulation and mRNA stabilization.<ref>PMID:9374458</ref><ref>PMID:10383454</ref> [[http://www.uniprot.org/uniprot/IRAK4_HUMAN IRAK4_HUMAN]] Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways. Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation to form the Myddosome together with IRAK2. Phosphorylates initially IRAK1, thus stimulating the kinase activity and intensive autophosphorylation of IRAK1. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates NCF1 and regulates NADPH oxidase activation after LPS stimulation suggesting a similar mechanism during microbial infections.<ref>PMID:11960013</ref><ref>PMID:12538665</ref><ref>PMID:15084582</ref><ref>PMID:17217339</ref><ref>PMID:17337443</ref><ref>PMID:17997719</ref><ref>PMID:20400509</ref>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.4&#8491;</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3mop FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3mop OCA], [https://pdbe.org/3mop PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3mop RCSB], [https://www.ebi.ac.uk/pdbsum/3mop PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3mop ProSAT]</span></td></tr>
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==About this Structure==
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</table>
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[[3mop]] is a 14 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3MOP OCA].
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== Disease ==
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[https://www.uniprot.org/uniprot/MYD88_HUMAN MYD88_HUMAN] Defects in MYD88 are the cause of MYD88 deficiency (MYD88D) [MIM:[https://omim.org/entry/612260 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>PMID:19506249</ref> <ref>PMID:18669862</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/MYD88_HUMAN MYD88_HUMAN] 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. Activates IRF1 resulting in its rapid migration into the nucleus to mediate an efficient induction of IFN-beta, NOS2/INOS, and IL12A genes (By similarity).<ref>PMID:9013863</ref> <ref>PMID:15361868</ref> <ref>PMID:18292575</ref> <ref>PMID:19506249</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/mo/3mop_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3mop ConSurf].
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<div style="clear:both"></div>
==See Also==
==See Also==
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*[[Interleukin-1 receptor-associated kinase 4|Interleukin-1 receptor-associated kinase 4]]
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*[[Interleukin-1 receptor-associated kinase|Interleukin-1 receptor-associated kinase]]
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*[[TIR domain-containing adapter protein|TIR domain-containing adapter protein]]
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==Reference==
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== References ==
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<ref group="xtra">PMID:020485341</ref><references group="xtra"/><references/>
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Non-specific serine/threonine protein kinase]]
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[[Category: Large Structures]]
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[[Category: Lin, S C.]]
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[[Category: Lin S-C]]
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[[Category: Lo, Y C.]]
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[[Category: Lo Y-C]]
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[[Category: Wu, H.]]
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[[Category: Wu H]]
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[[Category: Death domain complex]]
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[[Category: Helical symmetry]]
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[[Category: Immune system]]
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[[Category: Left-handed helical assembly]]
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[[Category: Signaling protein]]
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[[Category: Single-stranded helical assembly]]
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Current revision

The ternary Death Domain complex of MyD88, IRAK4, and IRAK2

PDB ID 3mop

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