Up to 50% of the population carry a single nucleotide polymorphism (SNP) in the gene encoding the inflammasome sensor Nlrp1. This SNP causes an amino acid exchange from methionine 1184 to valine (M1184V), and has been associated with several autoimmune syndromes. In collaboration with the Masters lab (The Walter and Eliza Hall Institute, Melbourne) we provide a molecular basis for the effects of this variant. By comparing the wild-type and M1184V proteins, we show that the M1184V mutation stabilizes the FIIND domain in a monomeric conformation. For full-length NLRP1, this effect translates as a stabilization of a multimeric conformation. Further, the variant displays increased DPP9 binding and as a result a higher capacity to capture free UPA-CARD fragments in inflammasome activation assays. The full study is now published in the Journal of Biological Chemistry...
