Molecular basis for peptidoglycan recognition by a bactericidal lectin

Rebecca E. Lehotzkya, Carrie L. Partchb, Sohini Mukherjeea, Heather L. Casha, William E. Goldman, Kevin H. Gardner, Lora V. Hooper

Research output: Contribution to journalArticle

85 Scopus citations

Abstract

RegIII proteins are secreted C-type lectins that kill Gram-positive bacteria and play a vital role in antimicrobial protection of the mammalian gut. RegIII proteins bind their bacterial targets via interactions with cell wall peptidoglycan but lack the canonical sequences that support calcium-dependent carbohydrate binding in other C-type lectins. Here, we use NMR spectroscopy to determine the molecular basis for peptidoglycan recognition by HIP/PAP, a human RegIII lectin. We show that HIP/PAP recognizes the peptidoglycan carbohydrate backbone in a calcium-independent manner via a conserved "EPN" motif that is critical for bacterial killing. While EPN sequences govern calcium-dependent carbohydrate recognition in other C-type lectins, the unusual location and calcium-independent functionality of the HIP/PAP EPN motif suggest that this sequence is a versatile functional module that can support both calcium-dependent and calcium-independent carbohydrate binding. Further, we show HIP/PAP binding affinity for carbohydrate ligands depends on carbohydrate chain length, supporting a binding model in which HIP/PAP molecules "bind and jump" along the extended polysaccharide chains of peptidoglycan, reducing dissociation rates and increasing binding affinity. We propose that dynamic recognition of highly clustered carbohydrate epitopes in native peptidoglycan is an essential mechanism governing high-affinity interactions between HIP/PAP and the bacterial cell wall.

Original languageEnglish (US)
Pages (from-to)7722-7727
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number17
DOIs
Publication statusPublished - Apr 27 2010

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Keywords

  • Antimicrobial protein
  • Bacterial cell wall
  • C-type lectin
  • Intestine
  • Nuclear magnetic resonance

ASJC Scopus subject areas

  • General

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