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Crystal structure of Drosophila PGRP-SD suggests binding to DAP-type but not lysine-type peptidoglycan
Philippe Leone1, Vincent Bischoff, Christine Kellenberger
1Architecture et Fonction des Macromolécules Biologiques, UMR 6098 CNRS and Universités Aix-Marseille I & II, Marseille, France.
Abstract:
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.
Insights
Peptidoglycan recognition protein SD (PGRP-SD) specifically recognizes diaminopimelic acid (DAP)-type peptidoglycans. This recognition is crucial for activating the Toll pathway in response to Gram-negative bacterial infections in Drosophila.
Area of Science:
- * Innate immunity
- * Molecular recognition
- * Drosophila melanogaster
Background:
- * Drosophila immune responses rely on Toll and immune deficiency (Imd) pathways.
- * Toll pathway senses Gram-positive bacteria and fungi; Imd pathway senses Gram-negative bacteria.
- * Peptidoglycan recognition proteins (PGRPs) are key in microbial recognition for the Toll pathway.
Purpose of the Study:
- * To elucidate the structural and functional role of PGRP-SD in Drosophila immunity.
- * To investigate PGRP-SD's specificity for peptidoglycan (PGN) ligands.
- * To understand PGRP-SD's contribution to Toll pathway activation.
Main Methods:
- * Crystal structure determination of PGRP-SD at 1.5Å resolution.
- * Comparison of PGRP-SD structure with known PGRP-ligand complexes.
- * Pull-down assays using insoluble peptidoglycans.
- * Analysis of Toll pathway activation in PGRP-SD mutant flies infected with specific bacteria.
Main Results:
- * The crystal structure of PGRP-SD was solved, suggesting specificity for diaminopimelic acid (DAP)-type peptidoglycans.
- * Pull-down assays confirmed PGRP-SD's binding preference for DAP-type PGNs.
- * PGRP-SD mutant flies exhibited reduced Toll pathway activation upon infection with DAP-type PGN-containing bacteria.
Conclusions:
- * PGRP-SD functions as a specific sensor for DAP-type peptidoglycans.
- * Recognition of DAP-type PGNs by PGRP-SD is essential for activating the Toll pathway against certain Gram-negative bacteria.
- * PGRP-SD plays a critical role in distinguishing microbial ligands to initiate appropriate immune responses.
