Structure of the Large Extracellular Loop of FtsX and Its Interaction with the Essential Peptidoglycan Hydrolase PcsB in <named-content content-type="genus-species">Streptococcus pneumoniae</named-content>

ABSTRACT Streptococcus pneumoniae is a leading killer of infants and immunocompromised adults and has become increasingly resistant to major antibiotics. Therefore, the development of new antibiotic strategies is desperately needed. Targeting bacterial cell division is one such strategy, specificall...

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Autores principales:	Britta E. Rued, Martín Alcorlo, Katherine A. Edmonds, Siseth Martínez-Caballero, Daniel Straume, Yue Fu, Kevin E. Bruce, Hongwei Wu, Leiv S. Håvarstein, Juan A. Hermoso, Malcolm E. Winkler, David P. Giedroc
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	NMR structure Streptococcus pneumoniae cell division peptidoglycan hydrolases protein-protein interactions Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/28bda687b8f04f1b9f23af1eaef5cc27
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spelling	oai:doaj.org-article:28bda687b8f04f1b9f23af1eaef5cc272021-11-15T15:55:14ZStructure of the Large Extracellular Loop of FtsX and Its Interaction with the Essential Peptidoglycan Hydrolase PcsB in <named-content content-type="genus-species">Streptococcus pneumoniae</named-content>10.1128/mBio.02622-182150-7511https://doaj.org/article/28bda687b8f04f1b9f23af1eaef5cc272019-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02622-18https://doaj.org/toc/2150-7511ABSTRACT Streptococcus pneumoniae is a leading killer of infants and immunocompromised adults and has become increasingly resistant to major antibiotics. Therefore, the development of new antibiotic strategies is desperately needed. Targeting bacterial cell division is one such strategy, specifically by targeting proteins that are essential for the synthesis and breakdown of peptidoglycan. One complex important to this process is FtsEX. FtsEX comprises a cell division-regulating integral membrane protein (FtsX) and a cytoplasmic ATPase (FtsE) that resembles an ATP-binding cassette (ABC) transporter. Here, we present nuclear magnetic resonance (NMR) solution structural and crystallographic models of the large extracellular domain of FtsX, denoted extracellular loop 1 (ECL1). The structure of ECL1 reveals an upper extended β-hairpin and a lower α-helical lobe, each extending from a mixed α-β core. The helical lobe mediates a physical interaction with the peptidoglycan hydrolase PcsB via the coiled-coil domain of PcsB (PscBCC). Characterization of S. pneumoniae strain D39-derived strains harboring mutations in the α-helical lobe shows that this subdomain is essential for cell viability and required for proper cell division of S. pneumoniae. IMPORTANCE FtsX is a ubiquitous bacterial integral membrane protein involved in cell division that regulates the activity of peptidoglycan (PG) hydrolases. FtsX is representative of a large group of ABC3 superfamily proteins that function as “mechanotransmitters,” proteins that relay signals from the inside to the outside of the cell. Here, we present a structural characterization of the large extracellular loop, ECL1, of FtsX from the opportunistic human pathogen S. pneumoniae. We show the molecular nature of the direct interaction between the peptidoglycan hydrolase PcsB and FtsX and demonstrate that this interaction is essential for cell viability. As such, FtsX represents an attractive, conserved target for the development of new classes of antibiotics.Britta E. RuedMartín AlcorloKatherine A. EdmondsSiseth Martínez-CaballeroDaniel StraumeYue FuKevin E. BruceHongwei WuLeiv S. HåvarsteinJuan A. HermosoMalcolm E. WinklerDavid P. GiedrocAmerican Society for MicrobiologyarticleNMR structureStreptococcus pneumoniaecell divisionpeptidoglycan hydrolasesprotein-protein interactionsMicrobiologyQR1-502ENmBio, Vol 10, Iss 1 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	NMR structure Streptococcus pneumoniae cell division peptidoglycan hydrolases protein-protein interactions Microbiology QR1-502
spellingShingle	NMR structure Streptococcus pneumoniae cell division peptidoglycan hydrolases protein-protein interactions Microbiology QR1-502 Britta E. Rued Martín Alcorlo Katherine A. Edmonds Siseth Martínez-Caballero Daniel Straume Yue Fu Kevin E. Bruce Hongwei Wu Leiv S. Håvarstein Juan A. Hermoso Malcolm E. Winkler David P. Giedroc Structure of the Large Extracellular Loop of FtsX and Its Interaction with the Essential Peptidoglycan Hydrolase PcsB in <named-content content-type="genus-species">Streptococcus pneumoniae</named-content>
description	ABSTRACT Streptococcus pneumoniae is a leading killer of infants and immunocompromised adults and has become increasingly resistant to major antibiotics. Therefore, the development of new antibiotic strategies is desperately needed. Targeting bacterial cell division is one such strategy, specifically by targeting proteins that are essential for the synthesis and breakdown of peptidoglycan. One complex important to this process is FtsEX. FtsEX comprises a cell division-regulating integral membrane protein (FtsX) and a cytoplasmic ATPase (FtsE) that resembles an ATP-binding cassette (ABC) transporter. Here, we present nuclear magnetic resonance (NMR) solution structural and crystallographic models of the large extracellular domain of FtsX, denoted extracellular loop 1 (ECL1). The structure of ECL1 reveals an upper extended β-hairpin and a lower α-helical lobe, each extending from a mixed α-β core. The helical lobe mediates a physical interaction with the peptidoglycan hydrolase PcsB via the coiled-coil domain of PcsB (PscBCC). Characterization of S. pneumoniae strain D39-derived strains harboring mutations in the α-helical lobe shows that this subdomain is essential for cell viability and required for proper cell division of S. pneumoniae. IMPORTANCE FtsX is a ubiquitous bacterial integral membrane protein involved in cell division that regulates the activity of peptidoglycan (PG) hydrolases. FtsX is representative of a large group of ABC3 superfamily proteins that function as “mechanotransmitters,” proteins that relay signals from the inside to the outside of the cell. Here, we present a structural characterization of the large extracellular loop, ECL1, of FtsX from the opportunistic human pathogen S. pneumoniae. We show the molecular nature of the direct interaction between the peptidoglycan hydrolase PcsB and FtsX and demonstrate that this interaction is essential for cell viability. As such, FtsX represents an attractive, conserved target for the development of new classes of antibiotics.
format	article
author	Britta E. Rued Martín Alcorlo Katherine A. Edmonds Siseth Martínez-Caballero Daniel Straume Yue Fu Kevin E. Bruce Hongwei Wu Leiv S. Håvarstein Juan A. Hermoso Malcolm E. Winkler David P. Giedroc
author_facet	Britta E. Rued Martín Alcorlo Katherine A. Edmonds Siseth Martínez-Caballero Daniel Straume Yue Fu Kevin E. Bruce Hongwei Wu Leiv S. Håvarstein Juan A. Hermoso Malcolm E. Winkler David P. Giedroc
author_sort	Britta E. Rued
title	Structure of the Large Extracellular Loop of FtsX and Its Interaction with the Essential Peptidoglycan Hydrolase PcsB in <named-content content-type="genus-species">Streptococcus pneumoniae</named-content>
title_short	Structure of the Large Extracellular Loop of FtsX and Its Interaction with the Essential Peptidoglycan Hydrolase PcsB in <named-content content-type="genus-species">Streptococcus pneumoniae</named-content>
title_full	Structure of the Large Extracellular Loop of FtsX and Its Interaction with the Essential Peptidoglycan Hydrolase PcsB in <named-content content-type="genus-species">Streptococcus pneumoniae</named-content>
title_fullStr	Structure of the Large Extracellular Loop of FtsX and Its Interaction with the Essential Peptidoglycan Hydrolase PcsB in <named-content content-type="genus-species">Streptococcus pneumoniae</named-content>
title_full_unstemmed	Structure of the Large Extracellular Loop of FtsX and Its Interaction with the Essential Peptidoglycan Hydrolase PcsB in <named-content content-type="genus-species">Streptococcus pneumoniae</named-content>
title_sort	structure of the large extracellular loop of ftsx and its interaction with the essential peptidoglycan hydrolase pcsb in <named-content content-type="genus-species">streptococcus pneumoniae</named-content>
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/28bda687b8f04f1b9f23af1eaef5cc27
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Structure of the Large Extracellular Loop of FtsX and Its Interaction with the Essential Peptidoglycan Hydrolase PcsB in <named-content content-type="genus-species">Streptococcus pneumoniae</named-content>

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