Metal Sequestration and Antimicrobial Activity of Human Calprotectin Are pH-Dependent

© 2020 American Chemical Society. Human calprotectin (CP, S100A8/S100A9 oligomer) is an abundant innate immune protein that sequesters transition metal ions in the extracellular space to limit nutrient availability and the growth of invading microbial pathogens. Our current understanding of the meta...

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Main Authors: Rosen, Tomer, Nolan, Elizabeth M
Other Authors: Massachusetts Institute of Technology. Department of Chemistry
Format: Article
Language:English
Published: American Chemical Society (ACS) 2021
Online Access:https://hdl.handle.net/1721.1/135317
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author Rosen, Tomer
Nolan, Elizabeth M
author2 Massachusetts Institute of Technology. Department of Chemistry
author_facet Massachusetts Institute of Technology. Department of Chemistry
Rosen, Tomer
Nolan, Elizabeth M
author_sort Rosen, Tomer
collection MIT
description © 2020 American Chemical Society. Human calprotectin (CP, S100A8/S100A9 oligomer) is an abundant innate immune protein that sequesters transition metal ions in the extracellular space to limit nutrient availability and the growth of invading microbial pathogens. Our current understanding of the metal-sequestering ability of CP is based on biochemical and functional studies performed at neutral or near-neutral pH. Nevertheless, CP can be present throughout the human body and is expressed at infection and inflammation sites that tend to be acidic. Here, we evaluate the metal binding and antimicrobial properties of CP in the pH range of 5.0-7.0. We show that Ca(II)-induced tetramerization, an important process for the extracellular functions of CP, is perturbed by acidic conditions. Moreover, a low pH impairs the antimicrobial activity of CP against some bacterial pathogens, including Staphylococcus aureus and Salmonella enterica serovar Typhimurium. At a mildly acidic pH, CP loses the ability to deplete Mn from microbial growth medium, indicating that Mn(II) sequestration is attenuated under acidic conditions. Evaluation of the Mn(II) binding properties of CP at pH 5.0-7.0 indicates that mildly acidic conditions decrease the Mn(II) binding affinity of the His6 site. Lastly, CP is less effective at preventing capture of Mn(II) by the bacterial solute-binding proteins MntC and PsaA at low pH. These results indicate that acidic conditions compromise the ability of CP to sequester Mn(II) and starve microbial pathogens of this nutrient. This work highlights the importance of considering the local pH of biological sites when describing the interplay between CP and microbes in host-pathogen interactions.
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spelling mit-1721.1/1353172023-10-05T19:27:40Z Metal Sequestration and Antimicrobial Activity of Human Calprotectin Are pH-Dependent Rosen, Tomer Nolan, Elizabeth M Massachusetts Institute of Technology. Department of Chemistry © 2020 American Chemical Society. Human calprotectin (CP, S100A8/S100A9 oligomer) is an abundant innate immune protein that sequesters transition metal ions in the extracellular space to limit nutrient availability and the growth of invading microbial pathogens. Our current understanding of the metal-sequestering ability of CP is based on biochemical and functional studies performed at neutral or near-neutral pH. Nevertheless, CP can be present throughout the human body and is expressed at infection and inflammation sites that tend to be acidic. Here, we evaluate the metal binding and antimicrobial properties of CP in the pH range of 5.0-7.0. We show that Ca(II)-induced tetramerization, an important process for the extracellular functions of CP, is perturbed by acidic conditions. Moreover, a low pH impairs the antimicrobial activity of CP against some bacterial pathogens, including Staphylococcus aureus and Salmonella enterica serovar Typhimurium. At a mildly acidic pH, CP loses the ability to deplete Mn from microbial growth medium, indicating that Mn(II) sequestration is attenuated under acidic conditions. Evaluation of the Mn(II) binding properties of CP at pH 5.0-7.0 indicates that mildly acidic conditions decrease the Mn(II) binding affinity of the His6 site. Lastly, CP is less effective at preventing capture of Mn(II) by the bacterial solute-binding proteins MntC and PsaA at low pH. These results indicate that acidic conditions compromise the ability of CP to sequester Mn(II) and starve microbial pathogens of this nutrient. This work highlights the importance of considering the local pH of biological sites when describing the interplay between CP and microbes in host-pathogen interactions. 2021-10-27T20:22:56Z 2021-10-27T20:22:56Z 2020 2021-07-14T17:47:03Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/135317 en 10.1021/ACS.BIOCHEM.0C00359 Biochemistry Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Chemical Society (ACS) PMC
spellingShingle Rosen, Tomer
Nolan, Elizabeth M
Metal Sequestration and Antimicrobial Activity of Human Calprotectin Are pH-Dependent
title Metal Sequestration and Antimicrobial Activity of Human Calprotectin Are pH-Dependent
title_full Metal Sequestration and Antimicrobial Activity of Human Calprotectin Are pH-Dependent
title_fullStr Metal Sequestration and Antimicrobial Activity of Human Calprotectin Are pH-Dependent
title_full_unstemmed Metal Sequestration and Antimicrobial Activity of Human Calprotectin Are pH-Dependent
title_short Metal Sequestration and Antimicrobial Activity of Human Calprotectin Are pH-Dependent
title_sort metal sequestration and antimicrobial activity of human calprotectin are ph dependent
url https://hdl.handle.net/1721.1/135317
work_keys_str_mv AT rosentomer metalsequestrationandantimicrobialactivityofhumancalprotectinarephdependent
AT nolanelizabethm metalsequestrationandantimicrobialactivityofhumancalprotectinarephdependent