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Crystal structure of a membrane-bound O-acyltransferase.

<div class='caption-title'>Overall structure of DltB and its conserved extracellular funnel.</div>
<div class='caption-title'>Structural basis of the DltB-DltC(Ppant) interaction.</div>
<div class='caption-title'>Structure of the DltB tunnel and the DltB-DltC(Ppant) binding mode provide insight into the molecular mechanism of DltB.</div>
Ma D, Wang Z, Merrikh CN, Lang KS, Lu P, Li X, Merrikh H, Rao Z, Xu W
OpenAccess logo Nature 562 286-290 (2018)
Related entries: 6bug, 6bui

Cited: 56 times
EuropePMC logo PMID: 30283133

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.

Reviews - 6buh mentioned but not cited (1)

  1. A rising tide lifts all MBOATs: recent progress in structural and functional understanding of membrane bound O-acyltransferases. Pierce MR, Hougland JL. Front Physiol 14 1167873 (2023)

Articles - 6buh mentioned but not cited (2)

  1. Crystal structure of a membrane-bound O-acyltransferase. Ma D, Wang Z, Merrikh CN, Lang KS, Lu P, Li X, Merrikh H, Rao Z, Xu W. Nature 562 286-290 (2018)
  2. Determination of the membrane topology of PORCN, an O-acyl transferase that modifies Wnt signalling proteins. Galli LM, Anderson MO, Gabriel Fraley J, Sanchez L, Bueno R, Hernandez DN, Maddox EU, Lingappa VR, Burrus LW. Open Biol 11 200400 (2021)


Reviews citing this publication (14)

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  38. The structure of phosphatidylinositol remodeling MBOAT7 reveals its catalytic mechanism and enables inhibitor identification. Wang K, Lee CW, Sui X, Kim S, Wang S, Higgs AB, Baublis AJ, Voth GA, Liao M, Walther TC, Farese RV. Nat Commun 14 3533 (2023)
  39. WssI from the Gram-negative bacterial cellulose synthase is an O-acetyltransferase that acts on cello-oligomers with several acetyl donor substrates. Burnett AJN, Rodriguez E, Constable S, Lowrance B, Fish M, Weadge JT. J Biol Chem 299 104849 (2023)


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