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      Helical assembly in the MyD88:IRAK4:IRAK2 complex in TLR/IL-1R signaling

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          Abstract

          MyD88, IRAK4 and IRAK2 are critical signaling 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 signaling 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 signaling 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 signaling in Drosophila and an elegant mechanism for versatile assembly and regulation of DD complexes in signal transduction.

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          Unresponsiveness of MyD88-deficient mice to endotoxin.

          MyD88 is a general adaptor protein that plays an important role in the Toll/IL-1 receptor family signalings. Recently, Toll-like receptors 2 and 4 (TLR2 and TLR4) have been suggested to be the signaling receptors for lipopolysaccharide (LPS). In this study, we demonstrate that MyD88 knockout mice lack the ability to respond to LPS as measured by shock response, B cell proliferative response, and secretion of cytokines by macrophages and embryonic fibroblasts. However, activation of neither NF-kappaB nor the mitogen-activated protein (MAP) kinase family is abolished in MyD88 knockout mice. These findings demonstrate that signaling via MyD88 is essential for LPS response, but the inability of MyD88 knockout mice to induce LPS-dependent gene expression cannot simply be attributed to lack of the activation of MAP kinases and NF-kappaB.
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            Shape complementarity at protein/protein interfaces.

            A new statistic Sc, which has a number of advantages over other measures of packing, is used to examine the shape complementarity of protein/protein interfaces selected from the Brookhaven Protein Data Bank. It is shown using Sc that antibody/antigen interfaces as a whole exhibit poorer shape complementarity than is observed in other systems involving protein/protein interactions. This result can be understood in terms of the fundamentally different evolutionary history of particular antibody/antigen associations compared to other systems considered, and in terms of the differing chemical natures of the interfaces.
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              Inferences, questions and possibilities in Toll-like receptor signalling.

              The Toll-like receptors (TLRs) are the key proteins that allow mammals--whether immunologically naive or experienced--to detect microbes. They lie at the core of our inherited resistance to disease, initiating most of the phenomena that occur in the course of infection. Quasi-infectious stimuli that have been used for decades to study inflammatory mechanisms can activate the TLR family of proteins. And it now seems that many inflammatory processes, both sterile and infectious, may depend on TLR signalling. We are in a good position to apply our understanding of TLR signalling to a range of challenges in immunology and medicine.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                0028-0836
                1476-4687
                6 May 2010
                19 May 2010
                17 June 2010
                1 December 2010
                : 465
                : 7300
                : 885-890
                Affiliations
                Department of Biochemistry, Weill Cornell Medical College, New York, NY 10021
                Author notes
                [* ]Correspondence to: Hao Wu, Ph.D., Department of Biochemistry, 1300 York Avenue, W-206, New York, NY 10021, Phone: 1-212-746-6451, Fax: 1-212-746-4843, haowu@ 123456med.cornell.edu
                Article
                nihpa200926
                10.1038/nature09121
                2888693
                20485341
                3ba3cf50-1348-4353-a525-e74b890c9f0c

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI050872-09 ||AI
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