Structural basis of RIP2 activation and signaling

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Structural basis of RIP2 activation and signaling
Structural basis of RIP2 activation and signaling
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Nature Communications
Publication Date:
26 November 2018
Gong, Q., Long, Z., Zhong, F.L. et al. Structural basis of RIP2 activation and signaling. Nat Commun 9, 4993 (2018).
Signals arising from bacterial infections are detected by pathogen recognition receptors (PRRs) and are transduced by specialized adapter proteins in mammalian cells. The Receptor-interacting-serine/threonine-protein kinase 2 (RIPK2 or RIP2) is such an adapter protein that is critical for signal propagation of the Nucleotide-binding-oligomerization-domain-containing proteins 1/2 (NOD1 and NOD2). Dysregulation of this signaling pathway leads to defects in bacterial detection and in some cases autoimmune diseases. Here, we show that the Caspase-activation-and-recruitment-domain (CARD) of RIP2 (RIP2-CARD) forms oligomeric structures upon stimulation by either NOD1-CARD or NOD2-2CARD. We reconstitute this complex, termed the RIPosome in vitro and solve the cryo-EM filament structure of the active RIP2-CARD complex at 4.1 Å resolution. The structure suggests potential mechanisms by which CARD domains from NOD1 and NOD2 initiate the oligomerization process of RIP2-CARD. Together with structure guided mutagenesis experiments at the CARD-CARD interfaces, we demonstrate molecular mechanisms how RIP2 is activated and self-propagating such signal.
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Funding Info:
This work was funded by NTU NAP SUG grant and Singapore Minister of Education Tier 2 Grant (MOE-2016-T2-1-010). The cryo-EM map has been deposited in the Electron Microscopy Databank with accession code EMD-6482. The atomic coordinate model has been deposited in the Protein Data Bank (PDB) with accession code 5YRN.
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