Intrinsic flexibility of NLRP pyrin domains is a key factor in their conformational dynamics, fold stability, and dimerization

Intrinsic flexibility of NLRP pyrin domains is a key factor in their conformational dynamics, fold stability, and dimerization
Title:
Intrinsic flexibility of NLRP pyrin domains is a key factor in their conformational dynamics, fold stability, and dimerization
Other Titles:
Protein Science
Keywords:
Publication Date:
17 November 2014
Citation:
Huber, R. G., Eibl, C. and Fuchs, J. E. (2015), Intrinsic flexibility of NLRP pyrin domains is a key factor in their conformational dynamics, fold stability, and dimerization. Protein Science, 24: 174-181. doi:10.1002/pro.2601
Abstract:
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.
License type:
PublisherCopyrights
Funding Info:
Austrian Science Fund; Grant number: FWF Project W_01213; Grant sponsor: Medical Research Council; Grant number: MR/K020919/1; Grant sponsor: Austrian Academy of Sciences (DOC Fellowship at University of Innsbruck).
Description:
Full paper can be downloaded from the Publisher's URL provided.
ISSN:
0961-8368
1469-896X
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