Structural and biochemical basis for induced self-propagation of NLRC4

Science. 2015 Oct 23;350(6259):399-404. doi: 10.1126/science.aac5489. Epub 2015 Oct 8.


Responding to stimuli, nucleotide-binding domain and leucine-rich repeat-containing proteins (NLRs) oligomerize into multiprotein complexes, termed inflammasomes, mediating innate immunity. Recognition of bacterial pathogens by NLR apoptosis inhibitory proteins (NAIPs) induces NLR family CARD domain-containing protein 4 (NLRC4) activation and formation of NAIP-NLRC4 inflammasomes. The wheel-like structure of a PrgJ-NAIP2-NLRC4 complex determined by cryogenic electron microscopy at 6.6 angstrom reveals that NLRC4 activation involves substantial structural reorganization that creates one oligomerization surface (catalytic surface). Once activated, NLRC4 uses this surface to catalyze the activation of an inactive NLRC4, self-propagating its active conformation to form the wheel-like architecture. NAIP proteins possess a catalytic surface matching the other oligomerization surface (receptor surface) of NLRC4 but not those of their own, ensuring that one NAIP is sufficient to initiate NLRC4 oligomerization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis Regulatory Proteins / chemistry*
  • Bacterial Proteins / chemistry
  • Calcium-Binding Proteins / chemistry*
  • Catalysis
  • Cryoelectron Microscopy
  • Immunity, Innate*
  • Inflammasomes / immunology
  • Mice
  • Molecular Sequence Data
  • Neuronal Apoptosis-Inhibitory Protein / chemistry*
  • Protein Conformation
  • Protein Multimerization


  • Apoptosis Regulatory Proteins
  • Bacterial Proteins
  • Calcium-Binding Proteins
  • Inflammasomes
  • Ipaf protein, mouse
  • Naip2 protein, mouse
  • Neuronal Apoptosis-Inhibitory Protein