Structural highlights
Publication Abstract from PubMed
Activation of the innate immune pattern recognition receptor NOD2 by the bacterial muramyl-dipeptide peptidoglycan fragment triggers recruitment of the downstream adaptor kinase RIP2, eventually leading to NF-kappaB activation and proinflammatory cytokine production. Here we show that full-length RIP2 can form long filaments mediated by its caspase recruitment domain (CARD), in common with other innate immune adaptor proteins. We further show that the NOD2 tandem CARDs bind to one end of the RIP2 CARD filament, suggesting a mechanism for polar filament nucleation by activated NOD2. We combine X-ray crystallography, solid-state NMR and high-resolution cryo-electron microscopy to determine the atomic structure of the helical RIP2 CARD filament, which reveals the intermolecular interactions that stabilize the assembly. Using structure-guided mutagenesis, we demonstrate the importance of RIP2 polymerization for the activation of NF-kappaB signalling by NOD2. Our results could be of use to develop new pharmacological strategies to treat inflammatory diseases characterised by aberrant NOD2 signalling.
RIP2 filament formation is required for NOD2 dependent NF-kappaB signalling.,Pellegrini E, Desfosses A, Wallmann A, Schulze WM, Rehbein K, Mas P, Signor L, Gaudon S, Zenkeviciute G, Hons M, Malet H, Gutsche I, Sachse C, Schoehn G, Oschkinat H, Cusack S Nat Commun. 2018 Oct 2;9(1):4043. doi: 10.1038/s41467-018-06451-3. PMID:30279485[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Pellegrini E, Desfosses A, Wallmann A, Schulze WM, Rehbein K, Mas P, Signor L, Gaudon S, Zenkeviciute G, Hons M, Malet H, Gutsche I, Sachse C, Schoehn G, Oschkinat H, Cusack S. RIP2 filament formation is required for NOD2 dependent NF-kappaB signalling. Nat Commun. 2018 Oct 2;9(1):4043. doi: 10.1038/s41467-018-06451-3. PMID:30279485 doi:http://dx.doi.org/10.1038/s41467-018-06451-3
