Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
Center for Plant Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
Cell Res. 2018 Jan;28(1):35-47. doi: 10.1038/cr.2017.148. Epub 2017 Nov 28.
The nucleotide-binding domain- and leucine-rich repeat (LRR)-containing proteins (NLRs) function as intracellular immune receptors to detect the presence of pathogen- or host-derived signals. The mechanisms of how NLRs sense their ligands remain elusive. Here we report the structure of a bacterial flagellin derivative in complex with the NLR proteins NAIP5 and NLRC4 determined by cryo-electron microscopy at 4.28 Å resolution. The structure revealed that the flagellin derivative forms two parallel helices interacting with multiple domains including BIR1 and LRR of NAIP5. Binding to NAIP5 results in a nearly complete burial of the flagellin derivative, thus stabilizing the active conformation of NAIP5. The extreme C-terminal side of the flagellin is anchored to a sterically constrained binding pocket of NAIP5, which likely acts as a structural determinant for discrimination of different bacterial flagellins by NAIP5, a notion further supported by biochemical data. Taken together, our results shed light on the molecular mechanisms underlying NLR ligand perception.
核苷酸结合域和富含亮氨酸重复（LRR）的蛋白（NLRs）作为细胞内免疫受体，用于检测病原体或宿主来源信号的存在。NLRs 如何感知其配体的机制仍不清楚。在此，我们通过冷冻电镜在 4.28 Å 的分辨率下，报道了一种细菌鞭毛蛋白衍生物与 NLR 蛋白 NAIP5 和 NLRC4 的复合物结构。该结构揭示了鞭毛蛋白衍生物形成两条平行的螺旋，与包括 NAIP5 的 BIR1 和 LRR 在内的多个结构域相互作用。与 NAIP5 的结合导致鞭毛蛋白衍生物几乎完全被掩埋，从而稳定了 NAIP5 的活性构象。鞭毛蛋白衍生物的极端 C 末端被锚定在 NAIP5 的空间受限结合口袋中，这可能是 NAIP5 区分不同细菌鞭毛蛋白的结构决定因素，这一观点得到了生化数据的进一步支持。总之，我们的研究结果揭示了 NLR 配体感知的分子机制。
