2a9i

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[[Image:2a9i.gif|left|200px]]<br /><applet load="2a9i" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="2a9i, resolution 1.70&Aring;" />
 
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'''Molecular Structure of the Interleukin-1 Receptor-Associated Kinase-4 Death Domain'''<br />
 
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==Overview==
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==Molecular Structure of the Interleukin-1 Receptor-Associated Kinase-4 Death Domain==
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IL-1R-associated kinase (IRAK) 4 is an essential component of innate immunity. IRAK-4 deficiency in mice and humans results in severe impairment of IL-1 and TLR signaling. We have solved the crystal structure for the death domain of Mus musculus IRAK-4 to 1.7 A resolution. This is the first glimpse of the structural details of a mammalian IRAK family member. The crystal structure reveals a six-helical bundle with a prominent loop, which among IRAKs and Pelle, a Drosophila homologue, is unique to IRAK-4. This highly structured loop contained between helices two and three, comprises an 11-aa stretch. Although innate immune domain recognition is thought to be very similar between Drosophila and mammals, this structural component points to a drastic difference. This structure can be used as a framework for future mutation and deletion studies and potential drug design.
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<StructureSection load='2a9i' size='340' side='right'caption='[[2a9i]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2a9i]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2A9I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2A9I FirstGlance]. <br>
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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]] 1.7&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene></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=2a9i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2a9i OCA], [https://pdbe.org/2a9i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2a9i RCSB], [https://www.ebi.ac.uk/pdbsum/2a9i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2a9i ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/IRAK4_MOUSE IRAK4_MOUSE] 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 (By similarity).
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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/a9/2a9i_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=2a9i ConSurf].
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<div style="clear:both"></div>
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==About this Structure==
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==See Also==
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2A9I is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with <scene name='pdbligand=MN:'>MN</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2A9I OCA].
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*[[Interleukin-1 receptor-associated kinase|Interleukin-1 receptor-associated kinase]]
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__TOC__
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==Reference==
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</StructureSection>
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Cutting edge: molecular structure of the IL-1R-associated kinase-4 death domain and its implications for TLR signaling., Lasker MV, Gajjar MM, Nair SK, J Immunol. 2005 Oct 1;175(7):4175-9. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16177054 16177054]
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[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Mus musculus]]
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[[Category: Non-specific serine/threonine protein kinase]]
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[[Category: Gajjar MM]]
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[[Category: Single protein]]
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[[Category: Lasker MV]]
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[[Category: Gajjar, M M.]]
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[[Category: Nair SK]]
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[[Category: Lasker, M V.]]
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[[Category: Nair, S K.]]
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[[Category: MN]]
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[[Category: hexahelical bundle]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:25:11 2008''
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Current revision

Molecular Structure of the Interleukin-1 Receptor-Associated Kinase-4 Death Domain

PDB ID 2a9i

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