Molecular Insight into TdfH-Mediated Zinc Piracy from Human Calprotectin by <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content>

ABSTRACT Neisseria gonorrhoeae, responsible for the sexually transmitted infection gonorrhea, is an obligate human pathogen exquisitely adapted for survival on mucosal surfaces of humans. This host-pathogen relationship has resulted in evolution by N. gonorrhoeae of pathways that enable the use of h...

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Autores principales:	Michael T. Kammerman, Aloke Bera, Runrun Wu, Simone A. Harrison, C. Noel Maxwell, Karl Lundquist, Nicholas Noinaj, Walter J. Chazin, Cynthia Nau Cornelissen
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	isothermal calorimetry calprotectin protein-protein interactions N. gonorrhoeae Neisseria gonorrhoeae TonB-dependent transporter Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/e6143808721949f8898784c762798033
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spelling	oai:doaj.org-article:e6143808721949f8898784c7627980332021-11-15T15:56:47ZMolecular Insight into TdfH-Mediated Zinc Piracy from Human Calprotectin by <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content>10.1128/mBio.00949-202150-7511https://doaj.org/article/e6143808721949f8898784c7627980332020-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00949-20https://doaj.org/toc/2150-7511ABSTRACT Neisseria gonorrhoeae, responsible for the sexually transmitted infection gonorrhea, is an obligate human pathogen exquisitely adapted for survival on mucosal surfaces of humans. This host-pathogen relationship has resulted in evolution by N. gonorrhoeae of pathways that enable the use of host metalloproteins as required nutrients through the deployment of outer membrane-bound TonB-dependent transporters (TdTs). Recently, a TdT called TdfH was implicated in binding to calprotectin (CP) and in removal of the bound zinc (Zn), enabling gonococcal growth. TdfH is highly conserved among the pathogenic Neisseria species, making it a potentially promising candidate for inclusion into a gonococcal vaccine. Currently, the nature and specificity of the TdfH-CP interaction have not been determined. In this study, we found that TdfH specifically interacted with human calprotectin (hCP) and that growth of the gonococcus was supported in a TdfH-dependent manner only when hCP was available as a sole zinc source and not when mouse CP was provided. The binding interactions between TdfH and hCP were assessed using isothermal titration calorimetry where we observed a multistate model having both high-affinity and low-affinity sites of interaction. hCP has two Zn binding sites, and gonococcal growth assays using hCP mutants deficient in one or both of the Zn binding sites revealed that TdfH exhibited a site preference during Zn piracy and utilization. This report provides the first insights into the molecular mechanism of Zn piracy by neisserial TdfH and further highlights the obligate human nature of N. gonorrhoeae and the high-affinity interactions occurring between TdTs and their human ligands during pathogenesis. IMPORTANCE The dramatic rise in antimicrobial resistance among Neisseria gonorrhoeae isolates over the last few decades, paired with dwindling treatment options and the lack of a protective vaccine, has prompted increased interest in identifying new bacterial targets for the treatment and, ideally, prevention of gonococcal disease. TonB-dependent transporters are a conserved set of proteins that serve crucial functions for bacterial survival within the host. In this study, binding between the gonococcal transporter, TdfH, and calprotectin was determined to be of high affinity and host restricted. The current study identified a preferential TdfH interaction at the calprotectin dimer interface. An antigonococcal therapeutic could potentially block this site on calprotectin, interrupting Zn uptake by N. gonorrhoeae and thereby prohibiting continued bacterial growth. We describe protein-protein interactions between TdfH and calprotectin, and our findings provide the building blocks for future therapeutic or prophylactic targets.Michael T. KammermanAloke BeraRunrun WuSimone A. HarrisonC. Noel MaxwellKarl LundquistNicholas NoinajWalter J. ChazinCynthia Nau CornelissenAmerican Society for Microbiologyarticleisothermal calorimetrycalprotectinprotein-protein interactionsN. gonorrhoeaeNeisseria gonorrhoeaeTonB-dependent transporterMicrobiologyQR1-502ENmBio, Vol 11, Iss 3 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	isothermal calorimetry calprotectin protein-protein interactions N. gonorrhoeae Neisseria gonorrhoeae TonB-dependent transporter Microbiology QR1-502
spellingShingle	isothermal calorimetry calprotectin protein-protein interactions N. gonorrhoeae Neisseria gonorrhoeae TonB-dependent transporter Microbiology QR1-502 Michael T. Kammerman Aloke Bera Runrun Wu Simone A. Harrison C. Noel Maxwell Karl Lundquist Nicholas Noinaj Walter J. Chazin Cynthia Nau Cornelissen Molecular Insight into TdfH-Mediated Zinc Piracy from Human Calprotectin by <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content>
description	ABSTRACT Neisseria gonorrhoeae, responsible for the sexually transmitted infection gonorrhea, is an obligate human pathogen exquisitely adapted for survival on mucosal surfaces of humans. This host-pathogen relationship has resulted in evolution by N. gonorrhoeae of pathways that enable the use of host metalloproteins as required nutrients through the deployment of outer membrane-bound TonB-dependent transporters (TdTs). Recently, a TdT called TdfH was implicated in binding to calprotectin (CP) and in removal of the bound zinc (Zn), enabling gonococcal growth. TdfH is highly conserved among the pathogenic Neisseria species, making it a potentially promising candidate for inclusion into a gonococcal vaccine. Currently, the nature and specificity of the TdfH-CP interaction have not been determined. In this study, we found that TdfH specifically interacted with human calprotectin (hCP) and that growth of the gonococcus was supported in a TdfH-dependent manner only when hCP was available as a sole zinc source and not when mouse CP was provided. The binding interactions between TdfH and hCP were assessed using isothermal titration calorimetry where we observed a multistate model having both high-affinity and low-affinity sites of interaction. hCP has two Zn binding sites, and gonococcal growth assays using hCP mutants deficient in one or both of the Zn binding sites revealed that TdfH exhibited a site preference during Zn piracy and utilization. This report provides the first insights into the molecular mechanism of Zn piracy by neisserial TdfH and further highlights the obligate human nature of N. gonorrhoeae and the high-affinity interactions occurring between TdTs and their human ligands during pathogenesis. IMPORTANCE The dramatic rise in antimicrobial resistance among Neisseria gonorrhoeae isolates over the last few decades, paired with dwindling treatment options and the lack of a protective vaccine, has prompted increased interest in identifying new bacterial targets for the treatment and, ideally, prevention of gonococcal disease. TonB-dependent transporters are a conserved set of proteins that serve crucial functions for bacterial survival within the host. In this study, binding between the gonococcal transporter, TdfH, and calprotectin was determined to be of high affinity and host restricted. The current study identified a preferential TdfH interaction at the calprotectin dimer interface. An antigonococcal therapeutic could potentially block this site on calprotectin, interrupting Zn uptake by N. gonorrhoeae and thereby prohibiting continued bacterial growth. We describe protein-protein interactions between TdfH and calprotectin, and our findings provide the building blocks for future therapeutic or prophylactic targets.
format	article
author	Michael T. Kammerman Aloke Bera Runrun Wu Simone A. Harrison C. Noel Maxwell Karl Lundquist Nicholas Noinaj Walter J. Chazin Cynthia Nau Cornelissen
author_facet	Michael T. Kammerman Aloke Bera Runrun Wu Simone A. Harrison C. Noel Maxwell Karl Lundquist Nicholas Noinaj Walter J. Chazin Cynthia Nau Cornelissen
author_sort	Michael T. Kammerman
title	Molecular Insight into TdfH-Mediated Zinc Piracy from Human Calprotectin by <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content>
title_short	Molecular Insight into TdfH-Mediated Zinc Piracy from Human Calprotectin by <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content>
title_full	Molecular Insight into TdfH-Mediated Zinc Piracy from Human Calprotectin by <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content>
title_fullStr	Molecular Insight into TdfH-Mediated Zinc Piracy from Human Calprotectin by <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content>
title_full_unstemmed	Molecular Insight into TdfH-Mediated Zinc Piracy from Human Calprotectin by <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content>
title_sort	molecular insight into tdfh-mediated zinc piracy from human calprotectin by <named-content content-type="genus-species">neisseria gonorrhoeae</named-content>
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/e6143808721949f8898784c762798033
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Molecular Insight into TdfH-Mediated Zinc Piracy from Human Calprotectin by <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content>

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