Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, AB T2N 4Z6, Canada.
Molecules. 2020 Oct 7;25(19):4572. doi: 10.3390/molecules25194572.
The prototypical model for NOD-like receptor (NLR) inflammasome assembly includes nucleotide-dependent activation of the NLR downstream of pathogen- or danger-associated molecular pattern (PAMP or DAMP) recognition, followed by nucleation of hetero-oligomeric platforms that lie upstream of inflammatory responses associated with innate immunity. As members of the STAND ATPases, the NLRs are generally thought to share a similar model of ATP-dependent activation and effect. However, recent observations have challenged this paradigm to reveal novel and complex biochemical processes to discern NLRs from other STAND proteins. In this review, we highlight past findings that identify the regulatory importance of conserved ATP-binding and hydrolysis motifs within the nucleotide-binding NACHT domain of NLRs and explore recent breakthroughs that generate connections between NLR protein structure and function. Indeed, newly deposited NLR structures for NLRC4 and NLRP3 have provided unique perspectives on the ATP-dependency of inflammasome activation. Novel molecular dynamic simulations of NLRP3 examined the active site of ADP- and ATP-bound models. The findings support distinctions in nucleotide-binding domain topology with occupancy of ATP or ADP that are in turn disseminated on to the global protein structure. Ultimately, studies continue to reveal how the ATP-binding and hydrolysis properties of NACHT domains in different NLRs integrate with signaling modules and binding partners to control innate immune responses at the molecular level.
NOD 样受体 (NLR) 炎性小体组装的典型模型包括病原体或危险相关分子模式 (PAMP 或 DAMP) 识别下游 NLR 的核苷酸依赖性激活，随后是位于先天免疫相关炎症反应上游的异源寡聚平台的成核。作为 STAND ATP 酶的成员，NLR 通常被认为具有相似的 ATP 依赖性激活和效应模型。然而，最近的观察结果挑战了这一范例，揭示了 NLR 与其他 STAND 蛋白区分开来的新的和复杂的生化过程。在这篇综述中，我们强调了过去的发现，这些发现确定了 NLR 中核苷酸结合 NACHT 结构域内保守的 ATP 结合和水解基序的调节重要性，并探讨了最近的突破，这些突破在 NLR 蛋白结构和功能之间建立了联系。事实上，NLRC4 和 NLRP3 的新 NLR 结构为炎性小体激活的 ATP 依赖性提供了独特的视角。NLRP3 的新型分子动力学模拟研究了 ADP 和 ATP 结合模型的活性位点。这些发现支持核苷酸结合结构域拓扑结构的区别，以及在全局蛋白质结构中传播的 ATP 或 ADP 的占据。最终，研究继续揭示不同 NLR 中的 NACHT 结构域的 ATP 结合和水解特性如何与信号模块和结合伙伴整合，以在分子水平上控制先天免疫反应。
