Structure of an Inner Membrane Protein Required for PhoPQ-Regulated Increases in Outer Membrane Cardiolipin

ABSTRACT The Salmonella enterica subsp. enterica serovar Typhimurium PhoPQ two-component system is activated within the intracellular phagosome environment, where it promotes remodeling of the outer membrane and resistance to innate immune antimicrobial peptides. Maintenance of the PhoPQ-regulated o...

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Autores principales:	Junping Fan, Erik M. Petersen, Thomas R. Hinds, Ning Zheng, Samuel I. Miller
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	PbgA CL transport PhoPQ outer membrane barrier salmonellae Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/37bede7359424917bc4367ca879c6ab8
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spelling	oai:doaj.org-article:37bede7359424917bc4367ca879c6ab82021-11-15T15:56:58ZStructure of an Inner Membrane Protein Required for PhoPQ-Regulated Increases in Outer Membrane Cardiolipin10.1128/mBio.03277-192150-7511https://doaj.org/article/37bede7359424917bc4367ca879c6ab82020-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.03277-19https://doaj.org/toc/2150-7511ABSTRACT The Salmonella enterica subsp. enterica serovar Typhimurium PhoPQ two-component system is activated within the intracellular phagosome environment, where it promotes remodeling of the outer membrane and resistance to innate immune antimicrobial peptides. Maintenance of the PhoPQ-regulated outer membrane barrier requires PbgA, an inner membrane protein with a transmembrane domain essential for growth, and a periplasmic domain required for PhoPQ-activated increases in outer membrane cardiolipin. Here, we report the crystal structure of cardiolipin-bound PbgA, adopting a novel transmembrane fold that features a cardiolipin binding site in close proximity to a long and deep cleft spanning the lipid bilayer. The end of the cleft extends into the periplasmic domain of the protein, which is structurally coupled to the transmembrane domain via a functionally critical C-terminal helix. In conjunction with a conserved putative catalytic dyad situated at the middle of the cleft, our structural and mutational analyses suggest that PbgA is a multifunction membrane protein that mediates cardiolipin transport, a function essential for growth, and perhaps catalysis of an unknown enzymatic reaction. IMPORTANCE Gram-negative bacteria cause many types of infections and have become increasingly resistant to available antibiotic drugs. The outer membrane serves as an important barrier that protects bacteria against antibiotics and other toxic compounds. This outer membrane barrier function is regulated when bacteria are in host environments, and the protein PbgA contributes significantly to this increased barrier function by transporting cardiolipin to the outer membrane. We determined the crystal structure of PbgA in complex with cardiolipin and propose a model for its function. Knowledge of the mechanisms of outer membrane assembly and integrity can greatly contribute to the development of new and effective antibiotics, and this structural information may be useful in this regard.Junping FanErik M. PetersenThomas R. HindsNing ZhengSamuel I. MillerAmerican Society for MicrobiologyarticlePbgACL transportPhoPQouter membrane barriersalmonellaeMicrobiologyQR1-502ENmBio, Vol 11, Iss 1 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	PbgA CL transport PhoPQ outer membrane barrier salmonellae Microbiology QR1-502
spellingShingle	PbgA CL transport PhoPQ outer membrane barrier salmonellae Microbiology QR1-502 Junping Fan Erik M. Petersen Thomas R. Hinds Ning Zheng Samuel I. Miller Structure of an Inner Membrane Protein Required for PhoPQ-Regulated Increases in Outer Membrane Cardiolipin
description	ABSTRACT The Salmonella enterica subsp. enterica serovar Typhimurium PhoPQ two-component system is activated within the intracellular phagosome environment, where it promotes remodeling of the outer membrane and resistance to innate immune antimicrobial peptides. Maintenance of the PhoPQ-regulated outer membrane barrier requires PbgA, an inner membrane protein with a transmembrane domain essential for growth, and a periplasmic domain required for PhoPQ-activated increases in outer membrane cardiolipin. Here, we report the crystal structure of cardiolipin-bound PbgA, adopting a novel transmembrane fold that features a cardiolipin binding site in close proximity to a long and deep cleft spanning the lipid bilayer. The end of the cleft extends into the periplasmic domain of the protein, which is structurally coupled to the transmembrane domain via a functionally critical C-terminal helix. In conjunction with a conserved putative catalytic dyad situated at the middle of the cleft, our structural and mutational analyses suggest that PbgA is a multifunction membrane protein that mediates cardiolipin transport, a function essential for growth, and perhaps catalysis of an unknown enzymatic reaction. IMPORTANCE Gram-negative bacteria cause many types of infections and have become increasingly resistant to available antibiotic drugs. The outer membrane serves as an important barrier that protects bacteria against antibiotics and other toxic compounds. This outer membrane barrier function is regulated when bacteria are in host environments, and the protein PbgA contributes significantly to this increased barrier function by transporting cardiolipin to the outer membrane. We determined the crystal structure of PbgA in complex with cardiolipin and propose a model for its function. Knowledge of the mechanisms of outer membrane assembly and integrity can greatly contribute to the development of new and effective antibiotics, and this structural information may be useful in this regard.
format	article
author	Junping Fan Erik M. Petersen Thomas R. Hinds Ning Zheng Samuel I. Miller
author_facet	Junping Fan Erik M. Petersen Thomas R. Hinds Ning Zheng Samuel I. Miller
author_sort	Junping Fan
title	Structure of an Inner Membrane Protein Required for PhoPQ-Regulated Increases in Outer Membrane Cardiolipin
title_short	Structure of an Inner Membrane Protein Required for PhoPQ-Regulated Increases in Outer Membrane Cardiolipin
title_full	Structure of an Inner Membrane Protein Required for PhoPQ-Regulated Increases in Outer Membrane Cardiolipin
title_fullStr	Structure of an Inner Membrane Protein Required for PhoPQ-Regulated Increases in Outer Membrane Cardiolipin
title_full_unstemmed	Structure of an Inner Membrane Protein Required for PhoPQ-Regulated Increases in Outer Membrane Cardiolipin
title_sort	structure of an inner membrane protein required for phopq-regulated increases in outer membrane cardiolipin
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/37bede7359424917bc4367ca879c6ab8
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Structure of an Inner Membrane Protein Required for PhoPQ-Regulated Increases in Outer Membrane Cardiolipin

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