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

Damo SM, Kehl-Fie TE, Sugitani N, Holt ME, Rathi S, Murphy WJ, Zhang Y, Betz C, Hench L, Fritz G, Skaar EP, Chazin WJ
Proc Natl Acad Sci U S A. 2013 110 (10): 3841-6

PMID: 23431180 · PMCID: PMC3593839 · DOI:10.1073/pnas.1220341110

The S100A8/S100A9 heterodimer calprotectin (CP) functions in the host response to pathogens through a mechanism termed "nutritional immunity." CP binds Mn(2+) and Zn(2+) with high affinity and starves bacteria of these essential nutrients. Combining biophysical, structural, and microbiological analysis, we identified the molecular basis of Mn(2+) sequestration. The asymmetry of the CP heterodimer creates a single Mn(2+)-binding site from six histidine residues, which distinguishes CP from all other Mn(2+)-binding proteins. Analysis of CP mutants with altered metal-binding properties revealed that, despite both Mn(2+) and Zn(2+) being essential metals, maximal growth inhibition of multiple bacterial pathogens requires Mn(2+) sequestration. These data establish the importance of Mn(2+) sequestration in defense against infection, explain the broad-spectrum antimicrobial activity of CP relative to other S100 proteins, and clarify the impact of metal depletion on the innate immune response to infection.

MeSH Terms (17)

Amino Acid Substitution Binding Sites Calgranulin A Calgranulin B Crystallography, X-Ray Histidine Host-Pathogen Interactions Humans Immunity, Innate Leukocyte L1 Antigen Complex Manganese Models, Molecular Mutagenesis, Site-Directed Protein Multimerization Recombinant Proteins Staphylococcus aureus Zinc

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