Extended Data Fig. 8: Mapping of pathogenic disease mutations in human NLRP3.

a, Structural mapping of all missense mutations listed in the Infevers database²³. Missense mutations are highlighted as spheres in light blue; validated, pathogenic mutations are marked in red. Although disease mutations are found in the entire protein, a particular accumulation is seen in the NBD of the NACHT domain. b, Overview of the 20 validated CAPS-associated pathogenic mutations from the Infevers database²³ with their predicted effect based on the NLRP3 structure. CAPS, Cryopyrin associated periodic syndrome; CINCA, chronic infantile neurological cutaneous articular; FCAS1, familial cold auto-inflammatory syndrome 1; NOMID, neonatal-onset multisystem inflammatory disorder; MWS, Muckle-Wells syndrome. c, Nineteen of twenty pathogenic NLRP3 mutations locate to an interface in the NACHT domain that shears upon activation. The proposed change to an ‘open’ conformation would lead to a disruption of the NBD to WHD/HD2 interface by a ~90° rotation in the linker region between HD1 and WHD. The rotation can be seen by the last helix of HD1 (coloured bordeaux) relative to the first helix of WD1 (coloured olive). The pathogenic mutations may disrupt the integrity of the interface between NBD and WHD/HD2, preventing NLRP3 from entering the resting state of the autoinhibited conformation. The CINCA mutation Y861C is the only residue outside the NACHT domain with a validated pathogenic phenotype. As Y861 interacts with the acidic loop, its mutation could affect the dimer formation mediated by interface A.