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4N1K: Crystal structures of NLRP14 pyrin domain reveal a conformational switch mechanism, regulating its molecular interactions
Structures of the NLRP14 pyrin domain reveal a conformational switch mechanism regulating its molecular interactions
Acta Crystallogr. D Biol. Crystallogr. (2014) 70 p.2007-2018
The cytosolic tripartite NLR receptors serve as important signalling platforms in innate immunity. While the C-terminal domains act as sensor and activation modules, the N-terminal death-like domain, e.g. the CARD or pyrin domain, is thought to recruit downstream effector molecules by homotypic interactions. Such homotypic complexes have been determined for all members of the death-domain superfamily except for pyrin domains. Here, crystal structures of human NLRP14 pyrin-domain variants are reported. The wild-type protein as well as the clinical D86V mutant reveal an unexpected rearrangement of the C-terminal helix alpha6, resulting in an extended alpha5/6 stem-helix. This reordering mediates a novel symmetric pyrin-domain dimerization mode. The conformational switching is controlled by a charge-relay system with a drastic impact on protein stability. How the identified charge relay allows classification of NLRP receptors with respect to distinct recruitment mechanisms is discussed.