A Drosophila pattern recognition receptor contains a peptidoglycan docking groove and unusual L,D-carboxypeptidase activity.

Abstract	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-A 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.
Authors	Chung-I Chang, Sébastien Pili-Floury, Mireille Hervé, Claudine Parquet, Yogarany Chelliah, Bruno Lemaitre, Dominique Mengin-Lecreulx, Johann Deisenhofer
Journal	PLoS biology (PLoS Biol) Vol. 2 Issue 9 Pg. E277 (Sep 2004) ISSN: 1545-7885 [Electronic] United States
PMID	15361936 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Carrier Proteins Drosophila Proteins Peptidoglycan Recombinant Proteins Tl protein, Drosophila Toll-Like Receptors imd protein, Drosophila peptidoglycan recognition protein Tyrosine Carboxypeptidases Lysine
Topics	Amino Acid Sequence Animals Binding Sites Carboxypeptidases (chemistry) Carrier Proteins (chemistry) Chromatography, High Pressure Liquid Crosses, Genetic Crystallography, X-Ray DNA Mutational Analysis Drosophila Proteins (metabolism) Drosophila melanogaster Hydrolysis Lysine (chemistry) Models, Molecular Molecular Sequence Data Mutagenesis, Site-Directed Mutation Peptidoglycan (chemistry) Protein Binding Protein Conformation Protein Structure, Secondary Recombinant Proteins (chemistry) Reverse Transcriptase Polymerase Chain Reaction Sequence Homology, Amino Acid Toll-Like Receptors (metabolism) Tyrosine (chemistry)

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