The N-terminal loop of IRAK-4 death domain regulates ordered assembly of the Myddosome signalling scaffold.
The N-terminal loop of IRAK-4 death domain regulates ordered assembly of the Myddosome signalling scaffold.
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DOI：
10.1038/srep37267
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发表时间：
2016-11-23
影响因子：
4.6
通讯作者：
Gay NJ
中科院分区：
文献类型：
--
作者：
Dossang AC;Motshwene PG;Yang Y;Symmons MF;Bryant CE;Borman S;George J;Weber AN;Gay NJ
激活Toll样受体会诱导二聚体（DD）适配器蛋白MyD88的募集到寡聚后的受体复合体中，Myddosome是炎症和致癌信号的枢纽。 Irak-4中的主题（Ser8-X-X-ARG12）是自动磷酸化的，并且磷酸化的DD无法形成myddosys，此外，在此位置上，具有磷酸化的dd dd。循环折叠到α-螺旋中。 Phosho-Ser8和Arg12之间的静电相互作用将破坏Irak-4和MyD88之间的临界界面。
Activation of Toll-like receptors induces dimerization and the recruitment of the death domain (DD) adaptor protein MyD88 into an oligomeric post receptor complex termed the Myddosome. The Myddosome is a hub for inflammatory and oncogenic signaling and has a hierarchical arrangement with 6–8 MyD88 molecules assembling with exactly 4 of IRAK-4 and 4 of IRAK-2. Here we show that a conserved motif in IRAK-4 (Ser8-X-X-X-Arg12) is autophosphorylated and that the phosphorylated DD is unable to form Myddosomes. Furthermore a mutant DD with the phospho-mimetic residue Asp at this position is impaired in both signalling and Myddosome assembly. IRAK-4 Arg12 is also essential for Myddosome assembly and signalling and we propose that phosphorylated Ser8 induces the N-terminal loop to fold into an α-helix. This conformer is stabilised by an electrostatic interaction between phospho-Ser8 and Arg12 and would destabilise a critical interface between IRAK-4 and MyD88. Interestingly IRAK-2 does not conserve this motif and has an alternative interface in the Myddosome that requires Arg67, a residue conserved in paralogues, IRAK-1 and 3(M).
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DOI：
10.1074/jbc.m110.159996
发表时间：
2011-01-14
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
George J;Motshwene PG;Wang H;Kubarenko AV;Rautanen A;Mills TC;Hill AV;Gay NJ;Weber AN
通讯作者：
Weber AN
影响因子：
4.8
作者：
Moncrieffe, Martin C.;Grossmann, J. Guenter;Gay, Nicholas J.
通讯作者：
Gay, Nicholas J.
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DOI：
10.1073/pnas.1418000111
发表时间：
2014-11-18
影响因子：
11.1
作者：
Hu, Qi;Wu, Di;Shi, Yigong
通讯作者：
Shi, Yigong
影响因子：
4.4
作者：
Lasker, MV;Gajjar, MM;Nair, SK
通讯作者：
Nair, SK
影响因子：
64.5
作者：
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通讯作者：
Wu, Hao