Leone Philippe, Bischoff Vincent, Kellenberger Christine, Hetru Charles, Royet Julien, Roussel Alain
Architecture et Fonction des Macromolécules Biologiques, UMR 6098 CNRS and Universités Aix-Marseille I & II, Marseille, France.
Mol Immunol. 2008 May;45(9):2521-30. doi: 10.1016/j.molimm.2008.01.015. Epub 2008 Mar 4.
In Drosophila the synthesis of antimicrobial peptides in response to microbial infections is under the control of the Toll and immune deficiency (Imd) signaling pathways. The Toll signaling pathway responds mainly to Gram-positive bacterial and fungal infection while the Imd pathway mediates the response to Gram-negative bacteria. Microbial recognition upstream of Toll involves, at least in part, peptidoglycan recognition proteins (PGRPs). The sensing of Gram-positive bacteria is mediated by the pattern recognition receptors PGRP-SA and Gram-negative binding protein 1 (GNBP1) that cooperate to detect the presence of lysine-type peptidoglycan in the host. Recently it has been shown that a loss-of-function mutation in peptidoglycan recognition protein SD (PGRP-SD) severely exacerbates the PGRP-SA and GNBP1 mutant phenotypes. Here we have solved the crystal structure of PGRP-SD at 1.5A resolution. Comparison with available structures of PGRPs in complex with their peptidoglycan (PGN) ligand strongly suggests a diaminopimelic acid (DAP) specificity for PGRP-SD. This result is supported by pull-down assays with insoluble PGNs. In addition we show that Toll pathway activation after infection by DAP-type PGN containing bacteria is clearly reduced in PGRP-SD mutant flies. Our hypothesis is that the role of PGRP-SD is the recognition of DAP-type PGNs responsible for the activation of the Toll pathway by Gram-negative bacteria.
在果蝇中，响应微生物感染而合成抗菌肽受Toll和免疫缺陷（Imd）信号通路的控制。Toll信号通路主要对革兰氏阳性菌和真菌感染作出反应，而Imd通路介导对革兰氏阴性菌的反应。Toll上游的微生物识别至少部分涉及肽聚糖识别蛋白（PGRP）。革兰氏阳性菌的感知由模式识别受体PGRP-SA和革兰氏阴性结合蛋白1（GNBP1）介导，它们共同协作以检测宿主体内赖氨酸型肽聚糖的存在。最近研究表明，肽聚糖识别蛋白SD（PGRP-SD）的功能丧失突变会严重加剧PGRP-SA和GNBP1突变体表型。在此，我们以1.5埃的分辨率解析了PGRP-SD的晶体结构。与PGRP与其肽聚糖（PGN）配体复合物的现有结构进行比较，强烈表明PGRP-SD对二氨基庚二酸（DAP）具有特异性。用不溶性PGN进行的下拉试验支持了这一结果。此外，我们表明，在PGRP-SD突变果蝇中，感染含DAP型PGN的细菌后Toll通路的激活明显减少。我们的假设是，PGRP-SD的作用是识别负责革兰氏阴性菌激活Toll通路的DAP型PGN。
