Structural anomalies in a published NMR-derived structure of IRAK-M

Poelman, Hessel; Ippel, Hans; Gürkan, Berke; Boelens, Rolf; Vriend, Gert; Veer, Cornelis van ’t; Lutgens, Esther; Nicolaes, Gerry A. F.

doi:10.1016/j.jmgm.2021.108061

Cited by 1 publication

(4 citation statements)

References 11 publications

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“…Arg97 of each of the IRAK-M subunits 1 to 4 is positioned to allow interaction with Asp19 of subunits that are 4 (n + 4) positions below it in the helix ( Figures 11A, B, F , 12A ). Lys60 of the subunits is positioned to interact with subunit n−1 ( Figures 11B, C , 12A ), possibly with Asp33 although this residue is also involved in a conserved intramolecular hydrogen bond ( Poelman et al, 2022 ). The position of IRAK-M residue Tyr105 is not well conserved in the death domain family but most probably positioned peripherally on the octamer without interacting points with the other IRAK-M DD subunits ( Supplementary Figure S4 ).…”

Section: Resultsmentioning

confidence: 99%

“…To substantiate our findings with structural information we performed a structural superposition of our recently published IRAK-DD homology model (Poelman et al, 2022) to each of the IRAK-4 and IRAK-2 subunits of PDBId:3MOP to obtain an octamer, assuming conservation of the three-dimensional orientation of DD complexes throughout the different DD organization modes. We then aligned the first four subunits of this octamer to the IRAK-4 layer of PDB ID:3MOP, so that the other four octamer subunits were positioned under this layer (Figure 11A)…”

Section: Structural Model For Myddosome and Homo Tetramer Formation O...mentioning

confidence: 85%

“…The IRAK-M octamer was constructed by superposition of a previously published homology model for the IRAK-M DD ( Poelman et al, 2022 ) to the IRAK-4 and IRAK-2 chains in PDB ID:3MOP ( Lin et al, 2010 ), using the MOTIF superposition algorithm in WHAT_IF ( Vriend, 1990 ). Four chains of the octamer were then superposed to the IRAK-2 layer of PDB ID:3MOP, such that the octamer was positioned under the IRAK-4 layer of PDB:3MOP.…”

Section: Methodsmentioning

confidence: 99%

“…Indicated are the borders of the domains, the secondary structure is shown from C to N terminal to fit the best view orientation with (B–D) . (B) Predicted IRAK-M Death Domain structure with identified functional residues indicated, based on the homology model by Poelman et al (2022) . (C) Schematic representation of IRAK-M Death Domain interaction surfaces as described by Lin et al (2010) .…”

Section: Introductionmentioning

confidence: 99%

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

Gürkan,

Poelman,

Pereverzeva

et al. 2024

Front. Mol. Biosci.

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Structural Model For Myddosome and Homo Tetramer Formation O...mentioning

confidence: 85%