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Title: A Drosophila Pattern Recognition Receptor Contains a Peptidoglycan Docking Groove and Unusual L,D-Carboxypeptidase Activity

Journal Article · · PLoS Biology (Online)
 [1];  [2];  [3];  [3];  [1];  [2];  [3];  [1]
  1. Univ. of Texas Southwestern Medical Center, Dallas, TX (United States). Howard Hughes Medical Inst. and Dept. of Biochemistry
  2. Centre National de la Recherche Scientifique (CNRS), Gif-sur-Yvette (France). Centre de Genetique Moleculaire
  3. Centre National de la Recherche Scientifique (CNRS), Gif-sur-Yvette (France). Institut de Biochimie et Biophysique Moleculaire et Cellulaire
+ Show Author Affiliations

The Drosophila peptidoglycan recognition protein SA (PGRP-SA) is critically involved in sensing bacterial infection and activating the Toll signaling pathway, which induces the expression of specific antimicrobial peptide genes. We have determined the crystal structure of PGRP-SA to 2.2-Å resolution and analyzed its peptidoglycan (PG) recognition and signaling activities. We found an extended surface groove in the structure of PGRP-SA, lined with residues that are highly diverse among different PGRPs. Mutational analysis identified it as a PG docking groove required for Toll signaling and showed that residue Ser158 is essential for both PG binding and Toll activation. Contrary to the general belief that PGRP-SA has lost enzyme function and serves primarily for PG sensing, we found that it possesses an intrinsic L,D-carboxypeptidase activity for diaminopimelic acid-type tetrapeptide PG fragments but not lysine-type PG fragments, and that Ser158 and His42 may participate in the hydrolytic activity. As L,D-configured peptide bonds exist only in prokaryotes, this work reveals a rare enzymatic activity in a eukaryotic protein known for sensing bacteria and provides a possible explanation of how PGRP-SA mediates Toll activation specifically in response to lysine-type PG.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division; Fondation Schlumberger
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1627130
Journal Information:
PLoS Biology (Online), Vol. 2, Issue 9; ISSN 1545-7885
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (34)

Crystal structure of peptidoglycan recognition protein SA in Apis mellifera (Hymenoptera: Apidae): Crystal Structure of PGRP-SA in A. mellifera journal March 2018
NF-κB/Rel Proteins and the Humoral Immune Responses of Drosophila melanogaster book January 2010
The Drosophila systemic immune response: sensing and signalling during bacterial and fungal infections journal November 2007
Peptidoglycan recognition proteins: pleiotropic sensors and effectors of antimicrobial defences journal April 2007
Sensing of Gram-positive bacteria in Drosophila: GNBP1 is needed to process and present peptidoglycan to PGRP-SA journal October 2006
Antimicrobial peptides from Bombyx mori : a splendid immune defense response in silkworms journal January 2020
Identification and molecular characterization of a novel protein Saglin as a target of monoclonal antibodies affecting salivary gland infectivity of Plasmodium sporozoites: Saglin, a putative receptor for malaria sporozoites journal December 2007
Bacterial recognition and signalling by the Drosophila IMD pathway: Drosophila immune recognition and signalling journal March 2005
Folds and activities of peptidoglycan amidases journal November 2007
Evolutionary origin of peptidoglycan recognition proteins in vertebrate innate immune system journal March 2011
Dehydration triggers ecdysone-mediated recognition-protein priming and elevated anti-bacterial immune responses in Drosophila Malpighian tubule renal cells journal May 2018
Relative Roles of the Cellular and Humoral Responses in the Drosophila Host Defense against Three Gram-Positive Bacterial Infections journal March 2011
Functional Analysis of PGRP-LA in Drosophila Immunity journal July 2013
Anopheles gambiae PGRPLC-Mediated Defense against Bacteria Modulates Infections with Malaria Parasites journal August 2009
PGRP-LD mediates A. stephensi vector competency by regulating homeostasis of microbiota-induced peritrophic matrix synthesis journal February 2018
Bacterial and fungal pattern recognition receptors in homologous innate signaling pathways of insects and mammals journal January 2015
Peptidoglycan recognition in Drosophila journal November 2007
Structure of the ectodomain of Drosophila peptidoglycan-recognition protein LCa suggests a molecular mechanism for pattern recognition journal July 2005
Clustering of peptidoglycan recognition protein-SA is required for sensing lysine-type peptidoglycan in insects journal April 2007
Crystal Structures of Bacterial Peptidoglycan Amidase AmpD and an Unprecedented Activation Mechanism* journal September 2011
Staphylococcus aureus Survives with a Minimal Peptidoglycan Synthesis Machine but Sacrifices Virulence and Antibiotic Resistance journal May 2015
Structural Insights into the Preferential Binding of PGRP-SAs from Bumblebees and Honeybees to Dap-Type Peptidoglycans Rather than Lys-Type Peptidoglycans journal December 2018
Bacterial recognition and signalling by the Drosophila IMD pathway: Drosophila immune recognition and signalling journal May 2005
Accessibility to Peptidoglycan Is Important for the Recognition of Gram-Positive Bacteria in Drosophila journal May 2019
Orthologous and Paralogous AmpD Peptidoglycan Amidases from Gram-Negative Bacteria journal September 2016
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Dehydration triggers ecdysone-mediated recognition-protein priming and elevated anti-bacterial immune responses in Drosophila Malpighian tubule renal cells journal May 2018
Functional Analysis of PGRP-LA in Drosophila Immunity journal July 2013
Anopheles gambiae PGRPLC-Mediated Defense against Bacteria Modulates Infections with Malaria Parasites journal August 2009
Wall Teichoic Acids of Staphylococcus aureus Limit Recognition by the Drosophila Peptidoglycan Recognition Protein-SA to Promote Pathogenicity journal December 2011
Staphylococcus aureus Survives with a Minimal Peptidoglycan Synthesis Machine but Sacrifices Virulence and Antibiotic Resistance journal May 2015
PGRP-LD mediates A. stephensi vector competency by regulating homeostasis of microbiota-induced peritrophic matrix synthesis journal February 2018
Bacterial and fungal pattern recognition receptors in homologous innate signaling pathways of insects and mammals journal January 2015

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Biochemistry & molecular biology
Life sciences & biomedicine - other topics
Pattern recognition receptors
Drosophila melanogaster
Crystal structure
Gram positive bacteria
Signal peptides
Bacterial diseases
Mutational analysis
Peptidoglycans