The phosphatidylglycerol phosphate synthase PgsA utilizes a trifurcated amphipathic cavity for catalysis at the membrane-cytosol interface

Phosphatidylglycerol is a crucial phospholipid found ubiquitously in biological membranes of prokaryotic and eukaryotic cells. The phosphatidylglycerol phosphate (PGP) synthase (PgsA), a membrane-embedded enzyme, catalyzes the primary reaction of phosphatidylglycerol biosynthesis. Mutations in pgsA...

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Autores principales:	Bowei Yang, Hebang Yao, Dianfan Li, Zhenfeng Liu
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Phosphatidylglycerol Synthase Staphylococcus aureus Daptomycin resistance Membrane protein Crystal structure Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/0ff6ec97c388461588eb84a09f42d98c
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spelling	oai:doaj.org-article:0ff6ec97c388461588eb84a09f42d98c2021-12-02T05:03:40ZThe phosphatidylglycerol phosphate synthase PgsA utilizes a trifurcated amphipathic cavity for catalysis at the membrane-cytosol interface2665-928X10.1016/j.crstbi.2021.11.005https://doaj.org/article/0ff6ec97c388461588eb84a09f42d98c2021-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2665928X21000283https://doaj.org/toc/2665-928XPhosphatidylglycerol is a crucial phospholipid found ubiquitously in biological membranes of prokaryotic and eukaryotic cells. The phosphatidylglycerol phosphate (PGP) synthase (PgsA), a membrane-embedded enzyme, catalyzes the primary reaction of phosphatidylglycerol biosynthesis. Mutations in pgsA frequently correlate with daptomycin resistance in Staphylococcus aureus and other prevalent infectious pathogens. Here we report the crystal structures of S. aureus PgsA (SaPgsA) captured at two distinct states of the catalytic process, with lipid substrate (cytidine diphosphate-diacylglycerol, CDP-DAG) or product (PGP) bound to the active site within a trifurcated amphipathic cavity. The hydrophilic head groups of CDP-DAG and PGP occupy two different pockets in the cavity, inducing local conformational changes. An elongated membrane-exposed surface groove accommodates the fatty acyl chains of CDP-DAG/PGP and opens a lateral portal for lipid entry/release. Remarkably, the daptomycin resistance-related mutations mostly cluster around the active site, causing reduction of enzymatic activity. Our results provide detailed mechanistic insights into the dynamic catalytic process of PgsA and structural frameworks beneficial for development of antimicrobial agents targeting PgsA from pathogenic bacteria.Bowei YangHebang YaoDianfan LiZhenfeng LiuElsevierarticlePhosphatidylglycerolSynthaseStaphylococcus aureusDaptomycin resistanceMembrane proteinCrystal structureBiology (General)QH301-705.5ENCurrent Research in Structural Biology, Vol 3, Iss , Pp 312-323 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Phosphatidylglycerol Synthase Staphylococcus aureus Daptomycin resistance Membrane protein Crystal structure Biology (General) QH301-705.5
spellingShingle	Phosphatidylglycerol Synthase Staphylococcus aureus Daptomycin resistance Membrane protein Crystal structure Biology (General) QH301-705.5 Bowei Yang Hebang Yao Dianfan Li Zhenfeng Liu The phosphatidylglycerol phosphate synthase PgsA utilizes a trifurcated amphipathic cavity for catalysis at the membrane-cytosol interface
description	Phosphatidylglycerol is a crucial phospholipid found ubiquitously in biological membranes of prokaryotic and eukaryotic cells. The phosphatidylglycerol phosphate (PGP) synthase (PgsA), a membrane-embedded enzyme, catalyzes the primary reaction of phosphatidylglycerol biosynthesis. Mutations in pgsA frequently correlate with daptomycin resistance in Staphylococcus aureus and other prevalent infectious pathogens. Here we report the crystal structures of S. aureus PgsA (SaPgsA) captured at two distinct states of the catalytic process, with lipid substrate (cytidine diphosphate-diacylglycerol, CDP-DAG) or product (PGP) bound to the active site within a trifurcated amphipathic cavity. The hydrophilic head groups of CDP-DAG and PGP occupy two different pockets in the cavity, inducing local conformational changes. An elongated membrane-exposed surface groove accommodates the fatty acyl chains of CDP-DAG/PGP and opens a lateral portal for lipid entry/release. Remarkably, the daptomycin resistance-related mutations mostly cluster around the active site, causing reduction of enzymatic activity. Our results provide detailed mechanistic insights into the dynamic catalytic process of PgsA and structural frameworks beneficial for development of antimicrobial agents targeting PgsA from pathogenic bacteria.
format	article
author	Bowei Yang Hebang Yao Dianfan Li Zhenfeng Liu
author_facet	Bowei Yang Hebang Yao Dianfan Li Zhenfeng Liu
author_sort	Bowei Yang
title	The phosphatidylglycerol phosphate synthase PgsA utilizes a trifurcated amphipathic cavity for catalysis at the membrane-cytosol interface
title_short	The phosphatidylglycerol phosphate synthase PgsA utilizes a trifurcated amphipathic cavity for catalysis at the membrane-cytosol interface
title_full	The phosphatidylglycerol phosphate synthase PgsA utilizes a trifurcated amphipathic cavity for catalysis at the membrane-cytosol interface
title_fullStr	The phosphatidylglycerol phosphate synthase PgsA utilizes a trifurcated amphipathic cavity for catalysis at the membrane-cytosol interface
title_full_unstemmed	The phosphatidylglycerol phosphate synthase PgsA utilizes a trifurcated amphipathic cavity for catalysis at the membrane-cytosol interface
title_sort	phosphatidylglycerol phosphate synthase pgsa utilizes a trifurcated amphipathic cavity for catalysis at the membrane-cytosol interface
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/0ff6ec97c388461588eb84a09f42d98c
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The phosphatidylglycerol phosphate synthase PgsA utilizes a trifurcated amphipathic cavity for catalysis at the membrane-cytosol interface

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