Huber Roland G, Eibl Clarissa, Fuchs Julian E
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.
Protein Sci. 2015 Feb;24(2):174-81. doi: 10.1002/pro.2601. Epub 2014 Dec 26.
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.
核苷酸结合结构域富含亮氨酸重复序列的受体（NLRs）是天然免疫系统中的关键蛋白。NLRs的NLRP家族的14个成员包含一个N端pyrin结构域，该结构域对于复合物形成和信号转导至关重要。最近，NLRP14的X射线结构揭示了pyrin结构域的α5/6茎螺旋发生了意外重排，从而产生了一种新的对称二聚化模式。我们使用分子动力学模拟来表征NLRP寡聚化背后的构象转变。我们描述了天然NLRP14及其单体和二聚体状态下突变体的构象稳定性，并将它们与天然pyrin结构域折叠的代表NLRP4进行比较。由此，我们表征了NLRP pyrin结构域中构象动力学、折叠稳定性和二聚化之间的相互作用。我们表明，NLRP pyrin结构域的内在灵活性是影响其在生理条件下行为的关键因素。此外，我们为NLRPs内电荷中继系统的至关重要性提供了进一步证据，该系统严重影响其在溶液中的构象集合。
