Document Detail


High-affinity manganese coordination by human calprotectin is calcium-dependent and requires the histidine-rich site formed at the dimer interface.
MedLine Citation:
PMID:  23276281     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Calprotectin (CP) is a transition metal-chelating antimicrobial protein of the calcium-binding S100 family that is produced and released by neutrophils. It inhibits the growth of various pathogenic microorganisms by sequestering the transition metal ions manganese and zinc. In this work, we investigate the manganese-binding properties of CP. We demonstrate that the unusual His(4) motif (site 2) formed at the S100A8/S100A9 dimer interface is the site of high-affinity Mn(II) coordination. We identify a low-temperature Mn(II) spectroscopic signal for this site consistent with an octahedral Mn(II) coordination sphere with simulated zero-field splitting parameters D = 270 MHz and E/D = 0.30 (E = 81 MHz). This analysis, combined with studies of mutant proteins, suggests that four histidine residues (H17 and H27 of S100A8; H91 and H95 of S100A9) coordinate Mn(II) in addition to two as-yet unidentified ligands. The His(3)Asp motif (site 1), which is also formed at the S100A8/S100A9 dimer interface, does not provide a high-affinity Mn(II) binding site. Calcium binding to the EF-hand domains of CP increases the Mn(II) affinity of the His(4) site from the low-micromolar to the mid-nanomolar range. Metal-ion selectivity studies demonstrate that CP prefers to coordinate Zn(II) over Mn(II). Nevertheless, the specificity of Mn(II) for the His(4) site provides CP with the propensity to form mixed Zn:Mn:CP complexes where one Zn(II) ion occupies site 1 and one Mn(II) ion occupies site 2. These studies support the notion that CP responds to physiological calcium ion gradients to become a high-affinity transition metal ion chelator in the extracellular space where it inhibits microbial growth.
Authors:
Joshua A Hayden; Megan Brunjes Brophy; Lisa S Cunden; Elizabeth M Nolan
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-12-31
Journal Detail:
Title:  Journal of the American Chemical Society     Volume:  135     ISSN:  1520-5126     ISO Abbreviation:  J. Am. Chem. Soc.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-16     Completed Date:  2013-06-19     Revised Date:  2014-01-23    
Medline Journal Info:
Nlm Unique ID:  7503056     Medline TA:  J Am Chem Soc     Country:  United States    
Other Details:
Languages:  eng     Pagination:  775-87     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Binding Sites
Calcium / chemistry
Dimerization
Histidine / chemistry*
Humans
Leukocyte L1 Antigen Complex / chemistry*,  metabolism
Manganese / chemistry*,  metabolism
Models, Molecular
Molecular Sequence Data
Sequence Alignment
Grant Support
ID/Acronym/Agency:
GM68762/GM/NIGMS NIH HHS; P30 ES002109/ES/NIEHS NIH HHS; P30-ES002109/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/Leukocyte L1 Antigen Complex; 42Z2K6ZL8P/Manganese; 4QD397987E/Histidine; SY7Q814VUP/Calcium
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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