The IRAK-M death domain: a tale of three surfaces.

Autor:	Gürkan B; Center of Experimental and Molecular Medicine, Amsterdam UMC Location University of Amsterdam, Amsterdam, Netherlands.; Amsterdam Infection and Immunity Institute, Amsterdam UMC Location University of Amsterdam, Amsterdam, Netherlands., Poelman H; Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands.; Medical Biochemistry, Amsterdam UMC Location University of Amsterdam, Amsterdam, Netherlands., Pereverzeva L; Center of Experimental and Molecular Medicine, Amsterdam UMC Location University of Amsterdam, Amsterdam, Netherlands.; Amsterdam Infection and Immunity Institute, Amsterdam UMC Location University of Amsterdam, Amsterdam, Netherlands., Kruijswijk D; Center of Experimental and Molecular Medicine, Amsterdam UMC Location University of Amsterdam, Amsterdam, Netherlands.; Amsterdam Infection and Immunity Institute, Amsterdam UMC Location University of Amsterdam, Amsterdam, Netherlands., de Vos AF; Center of Experimental and Molecular Medicine, Amsterdam UMC Location University of Amsterdam, Amsterdam, Netherlands.; Amsterdam Infection and Immunity Institute, Amsterdam UMC Location University of Amsterdam, Amsterdam, Netherlands., Groenen AG; Center of Experimental and Molecular Medicine, Amsterdam UMC Location University of Amsterdam, Amsterdam, Netherlands.; Amsterdam Infection and Immunity Institute, Amsterdam UMC Location University of Amsterdam, Amsterdam, Netherlands., Nollet EE; Center of Experimental and Molecular Medicine, Amsterdam UMC Location University of Amsterdam, Amsterdam, Netherlands.; Amsterdam Infection and Immunity Institute, Amsterdam UMC Location University of Amsterdam, Amsterdam, Netherlands., Wichapong K; Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands., Lutgens E; Medical Biochemistry, Amsterdam UMC Location University of Amsterdam, Amsterdam, Netherlands., van der Poll T; Center of Experimental and Molecular Medicine, Amsterdam UMC Location University of Amsterdam, Amsterdam, Netherlands.; Amsterdam Infection and Immunity Institute, Amsterdam UMC Location University of Amsterdam, Amsterdam, Netherlands.; Division of Infectious Diseases, Amsterdam UMC Location University of Amsterdam, Amsterdam, Netherlands., Du J; School of Life Sciences, Zhengzhou University, Zhengzhou, China., Wiersinga WJ; Center of Experimental and Molecular Medicine, Amsterdam UMC Location University of Amsterdam, Amsterdam, Netherlands.; Amsterdam Infection and Immunity Institute, Amsterdam UMC Location University of Amsterdam, Amsterdam, Netherlands.; Division of Infectious Diseases, Amsterdam UMC Location University of Amsterdam, Amsterdam, Netherlands., Nicolaes GAF; Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands.; Medical Biochemistry, Amsterdam UMC Location University of Amsterdam, Amsterdam, Netherlands., van 't Veer C; Center of Experimental and Molecular Medicine, Amsterdam UMC Location University of Amsterdam, Amsterdam, Netherlands.; Amsterdam Infection and Immunity Institute, Amsterdam UMC Location University of Amsterdam, Amsterdam, Netherlands.
Jazyk:	angličtina
Zdroj:	Frontiers in molecular biosciences [Front Mol Biosci] 2024 Jan 10; Vol. 10, pp. 1265455. Date of Electronic Publication: 2024 Jan 10 (Print Publication: 2023).
DOI:	10.3389/fmolb.2023.1265455
Abstrakt:	The anti-inflammatory interleukin-1 receptor associated kinase-M (IRAK-M) is a negative regulator of MyD88/IRAK-4/IRAK-1 signaling. However, IRAK-M has also been reported to activate NF-κB through the MyD88/IRAK-4/IRAK-M myddosome in a MEKK-3 dependent manner. Here we provide support that IRAK-M uses three surfaces of its Death Domain (DD) to activate NF-κB downstream of MyD88/IRAK-4/IRAK-M. Surface 1, with central residue Trp74, binds to MyD88/IRAK-4. Surface 2, with central Lys60, associates with other IRAK-M DDs to form an IRAK-M homotetramer under the MyD88/IRAK-4 scaffold. Surface 3; with central residue Arg97 is located on the opposite side of Trp74 in the IRAK-M DD tetramer, lacks any interaction points with the MyD88/IRAK-4 complex. Although the IRAK-M DD residue Arg97 is not directly involved in the association with MyD88/IRAK-4, Arg97 was responsible for 50% of the NF-κB activation though the MyD88/IRAK-4/IRAK-M myddosome. Arg97 was also found to be pivotal for IRAK-M's interaction with IRAK-1, and important for IRAK-M's interaction with TRAF6. Residue Arg97 was responsible for 50% of the NF-κB generated by MyD88/IRAK-4/IRAK-M myddosome in IRAK-1/MEKK3 double knockout cells. By structural modeling we found that the IRAK-M tetramer surface around Arg97 has excellent properties that allow formation of an IRAK-M homo-octamer. This model explains why mutation of Arg97 results in an IRAK-M molecule with increased inhibitory properties: it still binds to myddosome, competing with myddosome IRAK-1 binding, while resulting in less NF-κB formation. The findings further identify the structure-function properties of IRAK-M, which is a potential therapeutic target in inflammatory disease. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor TR declared a past collaboration with the author WW. (Copyright © 2024 Gürkan, Poelman, Pereverzeva, Kruijswijk, de Vos, Groenen, Nollet, Wichapong, Lutgens, van der Poll, Du, Wiersinga, Nicolaes and van ‘t Veer.)
Databáze:	MEDLINE
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