Fig. 1

Working model of the ATP binding cycle and activation of NLRP3 in inflammasome assembly.

Duncan Fig1

In this working model, NLRP3 is bound to nucleotide diphosphate (ADP, red triangle) in a closed (n) conformation in the basal state.  Activation of NLRP3 is induced by mutation, pathogen derived molecules (PAMPs), or other extracellular danger signals (DAMPs) (gold star) induces an open (c) conformation, allowing ADP/ATP exchange (ATP, red and green rectangle).  Hydrolysis of ATP to ADP with release of pyrophosphate (green triangle) by NLRP3 drives a conformational change to the activated (T) state, which then assembles with ASC, procaspase-1 to generate the pro-IL-1β-processing inflammasome.  This model presumes a NDP-bound basal state and a 1:1 caspase-1:NLRP3 stoichiometry in the active holoenzyme, which has not been demonstrated.  Other possibilities for the basal state of NLRP3 include ATP-bound with activation triggering nucleotide hydrolysis and release or empty NLRP3 with activation triggering opening of a nucleotide binding site