Intrinsic flexibility of NLRP pyrin domains is a key factor in their conformational dynamics, fold stability, and dimerization.
Nucleotide-binding domain leucine-rich repeat-containing receptors (NLRs) are key proteins in the innate immune system. The 14 members of the NLRP family of NLRs contain an N-terminal pyrin domain which is central for complex formation and signal transduction. Recently, X-ray structures of NLRP14 revealed an unexpected rearrangement of the α5/6 stem-helix of the pyrin domain allowing a novel symmetric dimerization mode. We characterize the conformational transitions underlying NLRP oligomerization using molecular dynamics simulations. We describe conformational stability of native NLRP14 and mutants in their monomeric and dimeric states and compare them to NLRP4, a representative of a native pyrin domain fold. Thereby, we characterize the interplay of conformational dynamics, fold stability, and dimerization in NLRP pyrin domains. We show that intrinsic flexibility of NLRP pyrin domains is a key factor influencing their behavior in physiological conditions. Additionally, we provide further evidence for the crucial importance of a charge relay system within NLRPs that critically influences their conformational ensemble in solution.
Institute for General, Inorganic and Theoretical Chemistry, Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain, 80/82, Innsbruck, Austria; Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), 30 Biopolis Street #07-01 Matrix, Singapore, 138671.
Roland G
RG
Huber
Clarissa
C
Eibl
Julian E
JE
Fuchs
D048868:Adaptor Proteins, Signal Transducing; D006801:Humans; D056004:Molecular Dynamics Simulation; D009154:Mutation; D043583:Nucleoside-Triphosphatase / Q000737:chemistry* / Q000235:genetics; D011487:Protein Conformation; D017510:Protein Folding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000737:chemistry*
D048868:Adaptor Proteins, Signal Transducing; C466775:NLRP4 protein, human; D012097:Repressor Proteins; C519485:NLRP14 protein, human; D043583:Nucleoside-Triphosphatase
NLRP dimerization; NLRP14 signaling; charge relay system; conformational dynamics; entropy; fold stability; molecular dynamics simulation; pyrin domain