Engagement of nucleotide-binding oligomerization domain-containing protein 1 (NOD1) by receptor interacting protein 2 (RIP2) is insufficient for signal transduction [Immunology]

June 23rd, 2014 by Mayle, S., Boyle, J. P., Sekine, E., Zurek, B., Kufer, T. A., Monie, T. P.

Following activation, the cytoplasmic pattern recognition receptor NOD1 interacts with its adaptor protein RIP2 to propagate immune signalling and initiate a pro-inflammatory immune response. This interaction is mediated by the caspase recruitment domain (CARD) of both proteins. Polymorphisms in immune proteins can affect receptor function and predispose individuals to specific autoinflammatory disorders. In this report, we have shown that mutations in helix 2 of the CARD of NOD1 disrupt receptor function, but do not interfere with RIP2 interaction. In particular Asn43Ser, a rare polymorphism, results in receptor dysfunction despite retaining normal cellular localisation, protein folding, and an ability to interact with RIP2. Mutation of Asn43 results in an increased tendency to form dimers, which we propose is the source of this dysfunction. We also demonstrate that mutation of Lys443 and Tyr474 in RIP2 disrupts the interaction with NOD1. Mapping the key residues involved in the interaction between NOD1 and RIP2 to the known structures of CARD complexes reveals the likely involvement of both type I and type III interfaces in the NOD1:RIP2 complex. Overall we demonstrate that the NOD1:RIP2 signalling axis is more complex than previously assumed, that simple engagement of RIP2 is insufficient to mediate signalling, and that the interaction between NOD1 and RIP2 constitutes multiple CARD:CARD interfaces.
  • Posted in Journal of Biological Chemistry, Publications
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