Research Article

Structural and biochemical basis for induced self-propagation of NLRC4

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Science  23 Oct 2015:
Vol. 350, Issue 6259, pp. 399-404
DOI: 10.1126/science.aac5489

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Inflammasomes take the wheel

Cells require microbial ligand binding to sense pathogens (see the Perspective by Liu and Xiao). Binding to the family of NOD-like receptors triggers the assembly of large protein signaling complexes called inflammasomes, leading infected cells to die and produce inflammatory mediators. Hu et al. and Zhang et al. use cryo–electron microscopy to uncover the structural and biochemical basis of two such receptors: NAIP2, which directly binds microbial ligands, and NLRC4, a protein functioning directly downstream. A self-propagating activation mechanism of downstream inflammasome signaling starts with one molecule of NAIP4 directly binding its microbial ligand. NAIP4 then catalyzes the activation of 10 to 12 NLRC4 molecules to form a wheel-like structure.

Science, this issue p. 399, 404; see also p. 376

Abstract

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.

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