Molecular basis for manganese sequestration by calprotectin and roles in the innate immune response to invading bacterial pathogens

Steven M. Damo, Thomas E. Kehl-Fie, Norie Sugitani, Marilyn E. Holt, Subodh Rathi, Wesley J. Murphy, Yaofang Zhang, Christine Betz, Laura Hench, Günter Fritz, Eric P. Skaar, Walter J. Chazin

Research output: Contribution to journalArticle

Abstract

The S100A8/S100A9 heterodimer calprotectin (CP) functions in the host response to pathogens through a mechanism termed "nutritional immunity." CP binds Mn2+ and Zn2+ with high affinity and starves bacteria of these essential nutrients. Combining biophysical, structural, and microbiological analysis, we identified the molecular basis of Mn2+ sequestration. The asymmetry of the CP heterodimer creates a single Mn2+-binding site from six histidine residues, which distinguishes CP from all other Mn2+-binding proteins. Analysis of CP mutants with altered metal-binding properties revealed that, despite bothMn2+ and Zn2+ being essentialmetals,maximal growth inhibition of multiple bacterial pathogens requires Mn2+ sequestration. These data establish the importance of Mn2+ sequestration in defense against infection, explain the broad- spectrumantimicrobial activity of CP relative to other S100 proteins, and clarify the impact of metal depletion on the innate immune response to infection.

Original languageEnglish (US)
Pages (from-to)3841-3846
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number10
DOIs
StatePublished - Mar 5 2013

Keywords

  • Antibiotic resistance
  • Bacterial pathogenesis
  • Isothermal titration calorimetry
  • Protein crystal structure
  • Staphylococcus aureus

ASJC Scopus subject areas

  • General

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