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4u97

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Revision as of 14:37, 10 May 2019

Crystal Structure of Asymmetric IRAK4 Dimer

Structural highlights

4u97 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	4u9a
Gene:	IRAK4 (HUMAN)
Activity:	Non-specific serine/threonine protein kinase, with EC number 2.7.11.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[IRAK4_HUMAN] Defects in IRAK4 are the cause of recurrent isolated invasive pneumococcal disease type 1 (IPD1) [MIM: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.^[1] Defects in IRAK4 are the cause of IRAK4 deficiency (IRAK4D) [MIM:607676]. IRAK4 deficiency causes extracellular pyogenic bacterial and fungal infections in otherwise healthy children.^[2] ^[3]

Function

[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.^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10]

Publication Abstract from PubMed

trans-autophosphorylation is among the most prevalent means of protein kinase activation, yet its molecular basis is poorly defined. In Toll-like receptor and interleukin-1 receptor signaling pathways, the kinase IRAK4 is recruited to the membrane-proximal adaptor MyD88 through death domain (DD) interactions, forming the oligomeric Myddosome and mediating NF-kappaB activation. Here we show that unphosphorylated IRAK4 dimerizes in solution with a KD of 2.5 muM and that Myddosome assembly greatly enhances IRAK4 kinase domain (KD) autophosphorylation at sub-KD concentrations. The crystal structure of the unphosphorylated IRAK4(KD) dimer captures a conformation that appears to represent the actual trans-autophosphorylation reaction, with the activation loop phosphosite of one IRAK4 monomer precisely positioned for phosphotransfer by its partner. We show that dimerization is crucial for IRAK4 autophosphorylation in vitro and ligand-dependent signaling in cells. These studies identify a mechanism for oligomerization-driven allosteric autoactivation of IRAK4 that may be general to other kinases activated by autophosphorylation.

IRAK4 Dimerization and trans-Autophosphorylation Are Induced by Myddosome Assembly.,Ferrao R, Zhou H, Shan Y, Liu Q, Li Q, Shaw DE, Li X, Wu H Mol Cell. 2014 Sep 18;55(6):891-903. doi: 10.1016/j.molcel.2014.08.006. Epub 2014, Sep 4. PMID:25201411^[11]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Ku CL, Picard C, Erdos M, Jeurissen A, Bustamante J, Puel A, von Bernuth H, Filipe-Santos O, Chang HH, Lawrence T, Raes M, Marodi L, Bossuyt X, Casanova JL. IRAK4 and NEMO mutations in otherwise healthy children with recurrent invasive pneumococcal disease. J Med Genet. 2007 Jan;44(1):16-23. Epub 2006 Sep 1. PMID:16950813 doi:jmg.2006.044446
↑ Medvedev AE, Lentschat A, Kuhns DB, Blanco JC, Salkowski C, Zhang S, Arditi M, Gallin JI, Vogel SN. Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections. J Exp Med. 2003 Aug 18;198(4):521-31. PMID:12925671 doi:http://dx.doi.org/10.1084/jem.20030701
↑ Picard C, Puel A, Bonnet M, Ku CL, Bustamante J, Yang K, Soudais C, Dupuis S, Feinberg J, Fieschi C, Elbim C, Hitchcock R, Lammas D, Davies G, Al-Ghonaium A, Al-Rayes H, Al-Jumaah S, Al-Hajjar S, Al-Mohsen IZ, Frayha HH, Rucker R, Hawn TR, Aderem A, Tufenkeji H, Haraguchi S, Day NK, Good RA, Gougerot-Pocidalo MA, Ozinsky A, Casanova JL. Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science. 2003 Mar 28;299(5615):2076-9. Epub 2003 Mar 13. PMID:12637671 doi:10.1126/science.1081902
↑ Li S, Strelow A, Fontana EJ, Wesche H. IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase. Proc Natl Acad Sci U S A. 2002 Apr 16;99(8):5567-72. PMID:11960013 doi:10.1073/pnas.082100399
↑ Burns K, Janssens S, Brissoni B, Olivos N, Beyaert R, Tschopp J. Inhibition of interleukin 1 receptor/Toll-like receptor signaling through the alternatively spliced, short form of MyD88 is due to its failure to recruit IRAK-4. J Exp Med. 2003 Jan 20;197(2):263-8. PMID:12538665
↑ Qin J, Jiang Z, Qian Y, Casanova JL, Li X. IRAK4 kinase activity is redundant for interleukin-1 (IL-1) receptor-associated kinase phosphorylation and IL-1 responsiveness. J Biol Chem. 2004 Jun 18;279(25):26748-53. Epub 2004 Apr 14. PMID:15084582 doi:10.1074/jbc.M400785200
↑ Pacquelet S, Johnson JL, Ellis BA, Brzezinska AA, Lane WS, Munafo DB, Catz SD. Cross-talk between IRAK-4 and the NADPH oxidase. Biochem J. 2007 May 1;403(3):451-61. PMID:17217339 doi:10.1042/BJ20061184
↑ Koziczak-Holbro M, Joyce C, Gluck A, Kinzel B, Muller M, Tschopp C, Mathison JC, Davis CN, Gram H. IRAK-4 kinase activity is required for interleukin-1 (IL-1) receptor- and toll-like receptor 7-mediated signaling and gene expression. J Biol Chem. 2007 May 4;282(18):13552-60. Epub 2007 Mar 2. PMID:17337443 doi:10.1074/jbc.M700548200
↑ Ordureau A, Smith H, Windheim M, Peggie M, Carrick E, Morrice N, Cohen P. The IRAK-catalysed activation of the E3 ligase function of Pellino isoforms induces the Lys63-linked polyubiquitination of IRAK1. Biochem J. 2008 Jan 1;409(1):43-52. PMID:17997719 doi:10.1042/BJ20071365
↑ Dunne A, Carpenter S, Brikos C, Gray P, Strelow A, Wesche H, Morrice N, O'Neill LA. IRAK1 and IRAK4 promote phosphorylation, ubiquitination, and degradation of MyD88 adaptor-like (Mal). J Biol Chem. 2010 Jun 11;285(24):18276-82. doi: 10.1074/jbc.M109.098137. Epub, 2010 Apr 16. PMID:20400509 doi:10.1074/jbc.M109.098137
↑ Ferrao R, Zhou H, Shan Y, Liu Q, Li Q, Shaw DE, Li X, Wu H. IRAK4 Dimerization and trans-Autophosphorylation Are Induced by Myddosome Assembly. Mol Cell. 2014 Sep 18;55(6):891-903. doi: 10.1016/j.molcel.2014.08.006. Epub 2014, Sep 4. PMID:25201411 doi:http://dx.doi.org/10.1016/j.molcel.2014.08.006

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4u97"

@@ Line 1: / Line 1: @@
 ==Crystal Structure of Asymmetric IRAK4 Dimer==
-<StructureSection load='4u97' size='340' side='right' caption='[[4u97]], [[Resolution|resolution]] 2.65&Aring;' scene=''>
+<StructureSection load='4u97' size='340' side='right'caption='[[4u97]], [[Resolution|resolution]] 2.65&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4u97]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4U97 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4U97 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4u97]] is a 2 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=4U97 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4U97 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=STU:STAUROSPORINE'>STU</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4u9a|4u9a]]</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">IRAK4 ([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='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=4u97 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4u97 OCA], [http://pdbe.org/4u97 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4u97 RCSB], [http://www.ebi.ac.uk/pdbsum/4u97 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4u97 ProSAT]</span></td></tr>
@@ Line 29: / Line 30: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Non-specific serine/threonine protein kinase]]
 [[Category: Ferrao, R]]

4u97

From Proteopedia

Revision as of 14:37, 10 May 2019

Crystal Structure of Asymmetric IRAK4 Dimer

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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