Mapping structural and dynamic divergence across the MBOAT family
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Abstract
Membrane-bound O-acyltransferases (MBOATs) are membrane-embedded enzymes that catalyze acyl chain transfer to a diverse group of substrates, including lipids, small molecules, and proteins. MBOATs share a conserved structural core, despite wide-ranging functional specificity across both prokaryotes and eukaryotes. The structural basis of catalytic specificity, regulation and interactions with the surrounding environment remain uncertain. Here, we combine comparative molecular dynamics (MD) simulations with bioinformatics to assess molecular and interactional divergence across the family. In simulations, MBOATs differentially distort the bilayer depending on their substrate type. Additionally, we identify lipid binding sites surrounding reactant gates in the surrounding membrane. Complementary bioinformatic analyses reveal a conserved role for re-entrant loop-2 in MBOAT fold stabilization and a key hydrogen bond bridging DGAT1 dimerization. Finally, we predict differences in MBOAT solvation and water gating properties. These data are pertinent to the design of MBOAT-specific inhibitors that encompass dynamic information within cellular mimetic environments.
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- Authors
- Ansell, T. B., Healy, M., Coupland, C. E., Sansom, M. S. P., & Siebold, C.
- Affiliations
- SLAC National Accelerator Laboratory (US)
- University of Oxford (GB)
- Centre for Human Genetics (GB)
- Corresponding author
- Ansell, T. Bertie
- Venue
- Structure
- Publisher
- Elsevier BV
- Published
- 2024-07
- Volume
- 32
- Issue
- 7
- Pages
- 1011-1022.e3
- ISSN
- 0969-2126 (ISSN-L)
- OpenAlex
- W4394893759
- Cited by
- 4
- References
- 67
- Citations by year
- 2026: 2 · 2025: 2
- FWCI
- 0.54
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Structure (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion, cc-by)
- Funders
- European Research Council (647278)
- Partnership for Advanced Computing In Europe (2016163984)
- Hospital for Sick Children (208361/Z/17/Z)
- Cancer Research UK (C20724 / A26752, DRCRPG-May23 / 100002)
- Wellcome Trust (102164/Z/13/Z)
- BBSRC (BB/R00126X/1, BB/T01508X/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- DGAT1, lipid binding sites, dimerization, hydrogen bonding, solvation, enzyme specificity
- MeSH terms
- Acyltransferases, Binding Sites, Humans, Hydrogen Bonding, Lipid Bilayers, Protein Binding, Substrate Specificity, Catalytic Domain, Protein Multimerization, Molecular Dynamics Simulation
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