Crystal structure of a membrane-bound O-acyltransferase
By D. Ma, Zhizhi Wang, Christopher Merrikh, Kevin S. Lang, P. Lu, Xin Li, Houra Merrikh, Z. Rao, Wenqing Xu. 2018
102 citations recorded by the source corpus.
Membrane-bound O-acyltransferases (MBOATs) are a superfamily of integral transmembrane enzymes that are found in all kingdoms of life1. In bacteria, MBOATs modify protective cell-surface polymers. In vertebrates, some MBOAT enzymes—such as acyl-coenzyme A:cholesterol acyltransferase and diacylglycerol acyltransferase 1—are responsible for lipid biosynthesis or phospholipid remodelling2,3. Other MBOATs, including porcupine, hedgehog acyltransferase and ghrelin acyltransferase, catalyse essential lipid modifications of secreted proteins such as Wnt, hedgehog and ghrelin, respectively4–10. Although many MBOAT proteins are important drug targets, little is known about their molecular architecture and functional mechanisms. Here we present crystal structures of DltB, an MBOAT responsible for the d-alanylation of cell-wall teichoic acid in Gram-positive bacteria11–16, both alone and in complex with the d-alanyl donor protein DltC. DltB contains a ring of 11 peripheral transmembrane helices, which shield a highly conserved extracellular structural funnel extending into the middle of the lipid bilayer. The conserved catalytic histidine residue is located at the bottom of this funnel and is connected to the intracellular DltC through a narrow tunnel. Mutation of either the catalytic histidine or the DltC-binding site of DltB abolishes the d-alanylation of lipoteichoic acid and sensitizes the Gram-positive bacterium Bacillus subtilis to cell-wall stress, which suggests cross-membrane catalysis involving the tunnel. Structure-guided sequence comparison among DltB and vertebrate MBOATs reveals a conserved structural core and suggests that MBOATs from different organisms have similar catalytic mechanisms. Our structures provide a template for understanding structure–function relationships in MBOATs and for developing therapeutic MBOAT inhibitors. Crystal structures of DltB, a bacterial membrane-bound O-acyltransferase, are reported both alone and in complex with the d-alanyl donor protein DltC.
Subfields: Materials Chemistry, Molecular Biology
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Citations in the corpus
- Structure, mechanism, and inhibition of Hedgehog acyltransferase (2021, background): “The majority of MBOATs 16, 2021 Crown Copyright ª 2021 Published by Elsevier Inc. 5025 er the CC BY license (http://creativecommons.org/licenses/by/4.0/). catalyze lipid chain transfer to small-molecule lipid substrates; however, HHAT, alongside porcupine acyltransferase (PORCN) and ghrelin O-acyltr”
- A specialized metabolic network selectively modulates Arabidopsis root microbiota (2019, unknown): “thaliana identified based on annotation (30) and found that only one of these [THAA3, At3g51970; previously reported to function in sterol fatty acid ester biosynthesis (31)] could catalyze the formation of thalianyl palmitate T18a when coexpressed with THAS in N.”
- Structural basis for catalysis and substrate specificity of human ACAT1 (2020, background): “To provide mechanistic insight into ACATs as well as other related MBOAT members, we determined the structure of full-length (FL) human ACAT1 at an overall resolution of 3.3 Å for the dimer of dimers and 3.0 Å for dimer only.”
- Structural model of PORCN illuminates disease-associated variants and drug binding sites (2021, unknown): “several human MBOAT family members have been determined that provided mechanistic insights into their enzymatic functions (Jiang et al., 2021; Long et al., 2020; Ma et al., 2018; Qian et al., 2020; Sui et al., 2020; Wang et al., 2020).”