title: Molecular basis for manganese sequestration by calprotectin and roles in the innate immune response to invading bacterial pathogens.
abstract: 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.
authors: Department of Biochemistry, and Center for Structural Biology, Vanderbilt University, Nashville, TN 37232-8725, USA.
authors: Steven M
authors: SM
authors: Damo
authors: Thomas E
authors: TE
authors: Kehl-Fie
authors: Norie
authors: N
authors: Sugitani
authors: Marilyn E
authors: ME
authors: Holt
authors: Subodh
authors: S
authors: Rathi
authors: Wesley J
authors: WJ
authors: Murphy
authors: Yaofang
authors: Y
authors: Zhang
authors: Christine
authors: C
authors: Betz
authors: Laura
authors: L
authors: Hench
authors: Günter
authors: G
authors: Fritz
authors: Eric P
authors: EP
authors: Skaar
authors: Walter J
authors: WJ
authors: Chazin
mesh_terms: D019943:Amino Acid Substitution; D001665:Binding Sites; D040501:Calgranulin A / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D040502:Calgranulin B / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D018360:Crystallography, X-Ray; D006639:Histidine / Q000737:chemistry; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D039841:Leukocyte L1 Antigen Complex / Q000737:chemistry* / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D008345:Manganese / Q000378:metabolism*; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D055503:Protein Multimerization; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development / Q000276:immunology; D015032:Zinc / Q000378:metabolism
chemical_list: D040501:Calgranulin A; D040502:Calgranulin B; D039841:Leukocyte L1 Antigen Complex; D011994:Recombinant Proteins; D008345:Manganese; D006639:Histidine; D015032:Zinc