4ewi | pdb_00004ewi
Crystal structure of the NLRP4 Pyrin domain
Structural highlights
FunctionNALP4_HUMAN May be involved in inflammation and recognition of cytosolic pathogen-associated molecular patterns (PAMPs) not intercepted by membrane-bound receptors. Acts as a negative regulator of the type I interferon signaling pathway by serving as an adapter to promote DTX4-mediated ubiquitination of activated TBK1, and its subsequent degradation. Suppresses NF-kappaB induction by the cytokines TNFA and IL1B, suggesting that it operates at a point of convergence in these two cytokine signaling pathways.[1] [2] Publication Abstract from PubMedNLRP4 is a member of the nucleotide-binding and leucine-rich repeat receptor (NLR) family of cytosolic receptors and a member of an inflammation signaling cascade. Here, we present the crystal structure of the NLRP4 pyrin domain (PYD) at 2.3 A resolution. The NLRP4 PYD is a member of the Death Domain (DD) superfamily and adopts a DD fold consisting of six alpha-helices tightly packed around a hydrophobic core, with a highly charged surface that is typical of PYDs. Importantly, however, we identified several differences between the NLRP4 PYD crystal structure and other PYD structures that are significant enough to affect NLRP4 function and its interactions with binding partners. Notably, the length of helix alpha3 and the alpha2-alpha3 connecting loop in NLRP4 PYD are unique among PYDs. The apoptosis-associated speck-like protein containing a CARD (ASC) is an adaptor protein whose interactions with a number of distinct PYDs is believed to be critical for activation of the inflammatory response. Here, we use co-immunoprecipitation, yeast two-hybrid and NMR chemical shift perturbation analysis to demonstrate that, despite being important for activation of the inflammatory response and sharing several similarities to other known ASC-interacting PYDs (i.e. ASC2), NLRP4 does not interact with the adaptor protein ASC. Thus, we propose that the factors governing homotypic PYD interactions are more complex than the currently accepted model, which states that complementary charged surfaces are the main determinants of PYD-PYD interaction specificity. Structural and Functional Analysis of the NLRP4 Pyrin domain.,Eibl C, Grigoriu S, Hessenberger M, Wenger J, Puehringer S, Pinheiro A, Wagner RN, Proell M, Reed JC, Page R, Diederichs K, Peti W Biochemistry. 2012 Aug 28. PMID:22928810[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||
