Crystal structure of a membrane-bound O-acyltransferase

Dan Ma, Zhizhi Wang, Christopher N. Merrikh, Kevin S. Lang, Peilong Lu, Xin Li, Houra Merrikh, Zihe Rao, Wenqing Xu

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)286-290
Number of pages5
JournalNature
Volume562
Issue number7726
DOIs
StatePublished - Oct 11 2018
Externally publishedYes

Bibliographical note

Funding Information:
Acknowledgements We are grateful to the staff at Advanced Light Source beamlines 5.0.1, 8.2.1 and 8.2.2 for assistance with synchrotron data collection. We thank N. Zheng and P. Hsu for comments on this manuscript, T. Hinds for discussion and advice on assays, S. Ovchinnikov for computational modelling, L. Kruse for use of the radioactive gel scanner and M. Ragheb for construction of the dlt operon deletion strain. This work was supported by National Institutes of Health grant R01 GM127316 to W.X. and a Jane Coffin Childs postdoctoral fellowship to D.M. This work was also supported by Chinese Academy of Sciences grant XDB08010303 to Z.R. and W.X., the National Institute of Health grant DP2GM110773 to H.M. and the Bacterial Pathogenesis Training Grant 5T32AI055396-13 to K.S.L.

Publisher Copyright:
© 2018, Springer Nature Limited.

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