3mop - Revision history

OCA at 10:26, 21 February 2024

2024-02-21T10:26:04Z

← Older revision		Revision as of 10:26, 21 February 2024
Line 1:		Line 1:

	==The ternary Death Domain complex of MyD88, IRAK4, and IRAK2==		==The ternary Death Domain complex of MyD88, IRAK4, and IRAK2==
	<StructureSection load='3mop' size='340' side='right' caption='[[3mop]], [[Resolution\|resolution]] 3.40Å' scene=''>		<StructureSection load='3mop' size='340' side='right'caption='[[3mop]], [[Resolution\|resolution]] 3.40Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[3mop]] is a 14 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Human Human~~]. 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 [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=3MOP FirstGlance]. <br>		<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>
	</td></tr><tr id='~~gene~~'><td class="sblockLbl"><b>[[~~Gene~~\|~~Gene~~:]]</b></td><td class="sblockDat"~~>MYD88 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), IRAK4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&~~id~~=9606 HUMAN]), IRAK2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>~~		</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 3.4Å</td></tr>
	~~<tr id='activity'><td class~~="~~sblockLbl~~">~~<b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non~~-~~specific serine/threonine protein kinase]~~, ~~with EC number~~ [~~http://www~~.~~brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span>~~</td></tr>		<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>
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=3mop FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3mop OCA], [~~http~~://pdbe.org/3mop PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=3mop RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/3mop PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=3mop ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
	[~~[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>		[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>
	== Function ==		== Function ==
	[~~[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>		[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>
	== Evolutionary Conservation ==		== Evolutionary Conservation ==
	[[Image:Consurf_key_small.gif\|200px\|right]]		[[Image:Consurf_key_small.gif\|200px\|right]]
	Check<jmol>		Check<jmol>
	<jmolCheckbox>		<jmolCheckbox>
	<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/mo/3mop_consurf.spt"</scriptWhenChecked>		<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/mo/3mop_consurf.spt"</scriptWhenChecked>
	<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>		<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
	<text>to colour the structure by Evolutionary Conservation</text>		<text>to colour the structure by Evolutionary Conservation</text>
Line 22:		Line 21:
	</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].		</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].
	<div style="clear:both"></div>		<div style="clear:both"></div>
	~~<div style="background-color:#fffaf0;">~~
	~~== Publication Abstract from PubMed ==~~
	MyD88, IRAK4 and IRAK2 are critical signalling mediators of the TLR/IL1-R superfamily. Here we report the crystal structure of the MyD88-IRAK4-IRAK2 death domain (DD) complex, which surprisingly reveals a left-handed helical oligomer that consists of 6 MyD88, 4 IRAK4 and 4 IRAK2 DDs. Assembly of this helical signalling tower is hierarchical, in which MyD88 recruits IRAK4 and the MyD88-IRAK4 complex recruits the IRAK4 substrates IRAK2 or the related IRAK1. Formation of these Myddosome complexes brings the kinase domains of IRAKs into proximity for phosphorylation and activation. Composite binding sites are required for recruitment of the individual DDs in the complex, which are confirmed by mutagenesis and previously identified signalling mutations. Specificities in Myddosome formation are dictated by both molecular complementarity and correspondence of surface electrostatics. The MyD88-IRAK4-IRAK2 complex provides a template for Toll signalling in Drosophila and an elegant mechanism for versatile assembly and regulation of DD complexes in signal transduction.

	~~Helical assembly in the MyD88~~-~~IRAK4~~-~~IRAK2 complex in TLR/IL~~-~~1R signalling.,Lin SC, Lo YC, Wu H Nature. 2010 Jun 17;465(7300):885~~-~~90. Epub 2010 May 19. PMID:20485341<ref>PMID:20485341</ref>~~		==See Also==
			*[[Interleukin-1 receptor-associated kinase\|Interleukin-1 receptor-associated kinase]]
	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~		*[[TIR domain-containing adapter protein\|TIR domain-containing adapter protein]]
	~~</div>~~
	~~<div class="pdbe~~-~~citations 3mop" style="background~~-~~color:#fffaf0;"></div>~~
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: ~~Human~~]]		[[Category: Homo sapiens]]
	[[Category: ~~Non-specific serine/threonine protein kinase~~]]		[[Category: Large Structures]]
	[[Category: Lin, S C]]		[[Category: Lin S-C]]
	[[Category: Lo, Y C]]		[[Category: Lo Y-C]]
	[[Category: Wu, H]]		[[Category: Wu H]]
	~~[[Category: Death domain complex]]~~
	~~[[Category: Helical symmetry]]~~
	~~[[Category: Immune system]]~~
	~~[[Category: Left-handed helical assembly]]~~
	~~[[Category: Signaling protein]]~~
	~~[[Category: Single-stranded helical assembly~~]]

OCA at 08:16, 8 November 2017

2017-11-08T08:16:09Z

← Older revision		Revision as of 08:16, 8 November 2017
Line 31:		Line 31:
	</div>		</div>
	<div class="pdbe-citations 3mop" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 3mop" style="background-color:#fffaf0;"></div>

	~~==See Also==~~
	*[[Interleukin-1 receptor-associated kinase\|Interleukin-1 receptor-associated kinase]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 01:56, 5 August 2016

2016-08-05T01:56:53Z

← Older revision		Revision as of 01:56, 5 August 2016
Line 1:		Line 1:

	==The ternary Death Domain complex of MyD88, IRAK4, and IRAK2==		==The ternary Death Domain complex of MyD88, IRAK4, and IRAK2==
	<StructureSection load='3mop' size='340' side='right' caption='[[3mop]], [[Resolution\|resolution]] 3.40Å' scene=''>		<StructureSection load='3mop' size='340' side='right' caption='[[3mop]], [[Resolution\|resolution]] 3.40Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[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]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3MOP FirstGlance]. <br>		<table><tr><td colspan='2'>[[3mop]] is a 14 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. 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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3MOP FirstGlance]. <br>
	</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">MYD88 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 ~~Homo sapiens~~]), IRAK4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 ~~Homo sapiens~~]), IRAK2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 ~~Homo sapiens~~])</td></tr>		</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">MYD88 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), IRAK4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), IRAK2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr>
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3mop FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3mop OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3mop RCSB], [http://www.ebi.ac.uk/pdbsum/3mop PDBsum]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3mop FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3mop OCA], [http://pdbe.org/3mop PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3mop RCSB], [http://www.ebi.ac.uk/pdbsum/3mop PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3mop ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 19:		Line 20:
	<text>to colour the structure by Evolutionary Conservation</text>		<text>to colour the structure by Evolutionary Conservation</text>
	</jmolCheckbox>		</jmolCheckbox>
	</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/~~chain_selection~~.php?pdb_ID=~~2ata~~ ConSurf].		</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].
	<div style="clear:both"></div>		<div style="clear:both"></div>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
Line 29:		Line 30:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
			<div class="pdbe-citations 3mop" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
	*[[Interleukin-1 receptor-associated kinase 4\|Interleukin-1 receptor-associated kinase 4]]		*[[Interleukin-1 receptor-associated kinase\|Interleukin-1 receptor-associated kinase]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: ~~Homo sapiens~~]]		[[Category: Human]]
	[[Category: Non-specific serine/threonine protein kinase]]		[[Category: Non-specific serine/threonine protein kinase]]
	[[Category: Lin, S C]]		[[Category: Lin, S C]]

OCA at 17:44, 18 December 2014

2014-12-18T17:44:20Z

← Older revision		Revision as of 17:44, 18 December 2014
Line 1:		Line 1:
	~~{{STRUCTURE_3mop~~\| ~~PDB~~=3mop \| ~~SCENE~~= }}		==The ternary Death Domain complex of MyD88, IRAK4, and IRAK2==
	===~~The ternary Death Domain~~ complex of MyD88, IRAK4, and IRAK2~~===~~		<StructureSection load='3mop' size='340' side='right' caption='[[3mop]], [[Resolution\|resolution]] 3.40Å' scene=''>
	~~{{ABSTRACT_PUBMED_20485341}}~~		== Structural highlights ==
			<table><tr><td colspan='2'>[[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]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3MOP FirstGlance]. <br>
			</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">MYD88 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]), IRAK4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]), IRAK2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
			<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr>
			<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3mop FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3mop OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3mop RCSB], [http://www.ebi.ac.uk/pdbsum/3mop PDBsum]</span></td></tr>
			</table>
			== Disease ==
			[[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>
			== Function ==
			[[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>
			== Evolutionary Conservation ==
			[[Image:Consurf_key_small.gif\|200px\|right]]
			Check<jmol>
			<jmolCheckbox>
			<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/mo/3mop_consurf.spt"</scriptWhenChecked>
			<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
			<text>to colour the structure by Evolutionary Conservation</text>
			</jmolCheckbox>
			</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/chain_selection.php?pdb_ID=2ata ConSurf].
			<div style="clear:both"></div>
			<div style="background-color:#fffaf0;">
			== Publication Abstract from PubMed ==
			MyD88, IRAK4 and IRAK2 are critical signalling mediators of the TLR/IL1-R superfamily. Here we report the crystal structure of the MyD88-IRAK4-IRAK2 death domain (DD) complex, which surprisingly reveals a left-handed helical oligomer that consists of 6 MyD88, 4 IRAK4 and 4 IRAK2 DDs. Assembly of this helical signalling tower is hierarchical, in which MyD88 recruits IRAK4 and the MyD88-IRAK4 complex recruits the IRAK4 substrates IRAK2 or the related IRAK1. Formation of these Myddosome complexes brings the kinase domains of IRAKs into proximity for phosphorylation and activation. Composite binding sites are required for recruitment of the individual DDs in the complex, which are confirmed by mutagenesis and previously identified signalling mutations. Specificities in Myddosome formation are dictated by both molecular complementarity and correspondence of surface electrostatics. The MyD88-IRAK4-IRAK2 complex provides a template for Toll signalling in Drosophila and an elegant mechanism for versatile assembly and regulation of DD complexes in signal transduction.

	~~==Disease==~~		Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling.,Lin SC, Lo YC, Wu H Nature. 2010 Jun 17;465(7300):885-90. Epub 2010 May 19. PMID:20485341<ref>PMID:20485341</ref>
	~~[[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>

	~~==Function==~~		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	~~[[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>~~		</div>

	~~==About this Structure==~~
	[[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].

	==See Also==		==See Also==
	*[[Interleukin-1 receptor-associated kinase 4\|Interleukin-1 receptor-associated kinase 4]]		*[[Interleukin-1 receptor-associated kinase 4\|Interleukin-1 receptor-associated kinase 4]]
			== References ==
	==~~Reference~~==		<references/>
	~~<ref group="xtra">PMID:020485341</ref>~~<references ~~group="xtra"~~/><~~references~~/>		__TOC__
			</StructureSection>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Non-specific serine/threonine protein kinase]]		[[Category: Non-specific serine/threonine protein kinase]]
	[[Category: Lin, S C.]]		[[Category: Lin, S C]]
	[[Category: Lo, Y C.]]		[[Category: Lo, Y C]]
	[[Category: Wu, H.]]		[[Category: Wu, H]]
	[[Category: Death domain complex]]		[[Category: Death domain complex]]
	[[Category: Helical symmetry]]		[[Category: Helical symmetry]]

OCA at 06:53, 25 March 2013

2013-03-25T06:53:55Z

← Older revision		Revision as of 06:53, 25 March 2013
Line 1:		Line 1:
	~~[[Image:3mop.png\|left\|200px]]~~

	{{STRUCTURE_3mop\| PDB=3mop \| SCENE= }}		{{STRUCTURE_3mop\| PDB=3mop \| SCENE= }}
			===The ternary Death Domain complex of MyD88, IRAK4, and IRAK2===
			{{ABSTRACT_PUBMED_20485341}}

	===~~The ternary Death Domain complex~~ of ~~MyD88~~, IRAK4, and ~~IRAK2===~~		==Disease==
			[[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>

	~~{{ABSTRACT_PUBMED_20485341}}~~		==Function==
			[[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>

	==About this Structure==		==About this Structure==
Line 14:		Line 16:

	==Reference==		==Reference==
	<ref group="xtra">PMID:020485341</ref><references group="xtra"/>		<ref group="xtra">PMID:020485341</ref><references group="xtra"/><references/>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Non-specific serine/threonine protein kinase]]		[[Category: Non-specific serine/threonine protein kinase]]

OCA at 09:28, 20 October 2012

2012-10-20T09:28:18Z

← Older revision		Revision as of 09:28, 20 October 2012
Line 8:		Line 8:

	==About this Structure==		==About this Structure==
	[[3mop]] is a 14 chain structure ~~of [[Interleukin-1 receptor-associated kinase 4]]~~ 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].		[[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].

	==See Also==		==See Also==

OCA: Protected "3mop" [edit=sysop:move=sysop]

2012-07-25T22:57:33Z

Protected "3mop" [edit=sysop:move=sysop]

← Older revision	Revision as of 22:57, 25 July 2012
(No difference)

OCA at 22:57, 25 July 2012

2012-07-25T22:57:30Z

← Older revision		Revision as of 22:57, 25 July 2012
Line 1:		Line 1:
	~~{{Seed}}~~
	[[Image:3mop.png\|left\|200px]]		[[Image:3mop.png\|left\|200px]]

	~~<!--~~
	~~The line below this paragraph, containing "STRUCTURE_3mop", creates the "Structure Box" on the page.~~
	~~You may change the PDB parameter (which sets the PDB file loaded into the applet)~~
	~~or the SCENE parameter (which sets the initial scene displayed when the page is loaded),~~
	~~or leave the SCENE parameter empty for the default display.~~
	~~-->~~
	{{STRUCTURE_3mop\| PDB=3mop \| SCENE= }}		{{STRUCTURE_3mop\| PDB=3mop \| SCENE= }}

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


	~~<!--~~
	~~The line below this paragraph, {{ABSTRACT_PUBMED_20485341}}, adds the Publication Abstract to the page~~
	~~(as it appears on PubMed at http://www.pubmed.gov), where 20485341 is the PubMed ID number.~~
	~~-->~~
	{{ABSTRACT_PUBMED_20485341}}		{{ABSTRACT_PUBMED_20485341}}

	==About this Structure==		==About this Structure==
	~~3MOP~~ is a 14 ~~chains~~ structure with ~~sequences~~ 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].		[[3mop]] is a 14 chain structure of [[Interleukin-1 receptor-associated kinase 4]] 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].

			==See Also==
			*[[Interleukin-1 receptor-associated kinase 4\|Interleukin-1 receptor-associated kinase 4]]

	==Reference==		==Reference==
	<ref group="xtra">PMID:~~20485341~~</ref><references group="xtra"/>		<ref group="xtra">PMID:020485341</ref><references group="xtra"/>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Non-specific serine/threonine protein kinase]]		[[Category: Non-specific serine/threonine protein kinase]]
Line 35:		Line 26:
	[[Category: Signaling protein]]		[[Category: Signaling protein]]
	[[Category: Single-stranded helical assembly]]		[[Category: Single-stranded helical assembly]]

	~~''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jun 23 08:35:21 2010''~~

OCA at 04:30, 23 June 2010

2010-06-23T04:30:03Z

← Older revision		Revision as of 04:30, 23 June 2010
Line 1:		Line 1:
	{{Seed}}		{{Seed}}
	[[Image:3mop.~~jpg~~\|left\|200px]]		[[Image:3mop.png\|left\|200px]]

	<!--		<!--
Line 18:		Line 18:
	-->		-->
	{{ABSTRACT_PUBMED_20485341}}		{{ABSTRACT_PUBMED_20485341}}

	~~==Disease==~~
	Known disease associated with this structure: Pyogenic bacterial infections, recurrent, due to MYD88 deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602170 602170]], IRAK4 deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606883 606883]], Invasive pneumococcal disease, recurrent isolated, 1 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606883 606883]]

	==About this Structure==		==About this Structure==
Line 39:		Line 36:
	[[Category: Single-stranded helical assembly]]		[[Category: Single-stranded helical assembly]]

	''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jun 2 08:34:14 2010''		''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jun 23 08:35:21 2010''

OCA at 04:29, 2 June 2010

2010-06-02T04:29:47Z

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
+{{Seed}}
-The entry 3mop is ON HOLD
+<!--
-Authors: Lin, S.-C., Lo, Y.-C., Wu, H.
+===The ternary Death Domain complex of MyD88, IRAK4, and IRAK2===
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed May  5 11:41:14 2010''
+<!--