title: Structures of the NLRP14 pyrin domain reveal a conformational switch mechanism regulating its molecular interactions.
abstract: 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 α6, resulting in an extended α5/6 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.
authors.affiliation: Department of Molecular Biology, University of Salzburg, Billrothstrasse 11, 5020 Salzburg, Austria.
authors.forename: Clarissa
authors.initials: C
authors.lastname: Eibl
authors.affiliation: Department of Molecular Biology, University of Salzburg, Billrothstrasse 11, 5020 Salzburg, Austria.
authors.forename: Manuel
authors.initials: M
authors.lastname: Hessenberger
authors.affiliation: Department of Molecular Biology, University of Salzburg, Billrothstrasse 11, 5020 Salzburg, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Wenger
authors.affiliation: Department of Molecular Biology, University of Salzburg, Billrothstrasse 11, 5020 Salzburg, Austria.
authors.forename: Hans
authors.initials: H
authors.lastname: Brandstetter
mesh_terms: D000595:Amino Acid Sequence; D002850:Chromatography, Gel; D002942:Circular Dichroism; D003598:Cytoskeletal Proteins / Q000737:chemistry*; D006801:Humans; D008969:Molecular Sequence Data; D043583:Nucleoside-Triphosphatase / Q000737:chemistry*; D011487:Protein Conformation; D000071198:Pyrin; D017386:Sequence Homology, Amino Acid
chemical_list: D003598:Cytoskeletal Proteins; C000604192:MEFV protein, human; D000071198:Pyrin; C519485:NLRP14 protein, human; D043583:Nucleoside-Triphosphatase
keywords: NLRP14; pyrin domain