Journal article
Molecular basis for manganese sequestration by calprotectin and roles in the innate immune response to invading bacterial pathogens
Proceedings of the National Academy of Sciences - PNAS, Vol.110(10), pp.3841-3846
03/05/2013
DOI: 10.1073/pnas.1220341110
PMCID: PMC3593839
PMID: 23431180
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 both Mn2+ and Zn2+ being essential metals, 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-spectrum antimicrobial activity of CP relative to other S100 proteins, and clarify the impact of metal depletion on the innate immune response to infection.
Details
- Title: Subtitle
- Molecular basis for manganese sequestration by calprotectin and roles in the innate immune response to invading bacterial pathogens
- Creators
- Steven M. Damo - Vanderbilt UniversityThomas E. Kehl-Fie - Vanderbilt UniversityNorie Sugitani - Vanderbilt UniversityMarilyn E. Holt - Vanderbilt UniversitySubodh Rathi - Vanderbilt UniversityWesley J. Murphy - Vanderbilt UniversityYaofang Zhang - Vanderbilt UniversityChristine Betz - University of FreiburgLaura Hench - Vanderbilt UniversityGuenter Fritz - University of FreiburgEric P. Skaar - Vanderbilt UniversityWalter J. Chazin - Vanderbilt University
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.110(10), pp.3841-3846
- Publisher
- Natl Acad Sciences
- DOI
- 10.1073/pnas.1220341110
- PMID
- 23431180
- PMCID
- PMC3593839
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Number of pages
- 6
- Grant note
- 085P1000817 / Michigan Technology Tri-Corridor R01AI069233 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) T32CA009582 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) T32HL094296 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) FR 1488/3-1 / Heisenberg fellowship of the Deutsche Forschungsgemeinschaft; German Research Foundation (DFG) T32 CA009582; T32 HL094296; R56 AI091771; R01 AI101171; R01 AI069233; R01 AI073843; R01 GM62122-S1 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA American Heart Postdoctoral Fellowship Michigan Economic Development Corporation DE-AC02-06CH11357 / US Department of Energy, Office of Science, Office of Basic Energy Sciences; United States Department of Energy (DOE) P30ES000267 / NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Environmental Health Sciences (NIEHS) R01MH062122 / NATIONAL INSTITUTE OF MENTAL HEALTH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH) National Science Foundation-Research Experiences for Undergraduates program at Vanderbilt University
- Language
- English
- Date published
- 03/05/2013
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984618517302771
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