The structure of phosphatidylinositol remodeling MBOAT7 reveals its catalytic mechanism and enables inhibitor identification

Kun Wang; Chia-Wei Lee; Xuewu Sui; Siyoung Kim; Shuhui Wang; Aidan B Higgs; Aaron J Baublis; Gregory A Voth; Maofu Liao; Tobias C Walther; Robert V Farese Jr

doi:10.1038/s41467-023-38932-5

The structure of phosphatidylinositol remodeling MBOAT7 reveals its catalytic mechanism and enables inhibitor identification

Nat Commun. 2023 Jun 14;14(1):3533. doi: 10.1038/s41467-023-38932-5.

Authors

Kun Wang^{1

2}, Chia-Wei Lee^{1

2}, Xuewu Sui^{1

2

3}, Siyoung Kim⁴, Shuhui Wang², Aidan B Higgs^{1

2}, Aaron J Baublis^{1

2

5}, Gregory A Voth⁶, Maofu Liao^#^{7

8}, Tobias C Walther^#^{9

10

11

12

13

14}, Robert V Farese Jr^#^{15

16

17

18}

Affiliations

¹ Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
² Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
³ Department of Biochemistry and Biophysics, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX, USA.
⁴ Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA.
⁵ Harvard T.H. Chan Advanced Multi-Omics Platform, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁶ Department of Chemistry, Chicago Center for Theoretical Chemistry, James Franck Institute, and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL, USA.
⁷ Department of Cell Biology, Harvard Medical School, Boston, MA, USA. liaomf@sustech.edu.cn.
⁸ School of Life Sciences, Southern University of Science and Technology, Shenzhen, China. liaomf@sustech.edu.cn.
⁹ Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA. twalther@mskcc.org.
¹⁰ Department of Cell Biology, Harvard Medical School, Boston, MA, USA. twalther@mskcc.org.
¹¹ Harvard T.H. Chan Advanced Multi-Omics Platform, Harvard T.H. Chan School of Public Health, Boston, MA, USA. twalther@mskcc.org.
¹² Broad Institute of MIT and Harvard, Cambridge, MA, USA. twalther@mskcc.org.
¹³ Howard Hughes Medical Institute, Boston, MA, USA. twalther@mskcc.org.
¹⁴ Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. twalther@mskcc.org.
¹⁵ Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA. rfarese@mskcc.org.
¹⁶ Department of Cell Biology, Harvard Medical School, Boston, MA, USA. rfarese@mskcc.org.
¹⁷ Broad Institute of MIT and Harvard, Cambridge, MA, USA. rfarese@mskcc.org.
¹⁸ Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. rfarese@mskcc.org.

^# Contributed equally.

Abstract

Cells remodel glycerophospholipid acyl chains via the Lands cycle to adjust membrane properties. Membrane-bound O-acyltransferase (MBOAT) 7 acylates lyso-phosphatidylinositol (lyso-PI) with arachidonyl-CoA. MBOAT7 mutations cause brain developmental disorders, and reduced expression is linked to fatty liver disease. In contrast, increased MBOAT7 expression is linked to hepatocellular and renal cancers. The mechanistic basis of MBOAT7 catalysis and substrate selectivity are unknown. Here, we report the structure and a model for the catalytic mechanism of human MBOAT7. Arachidonyl-CoA and lyso-PI access the catalytic center through a twisted tunnel from the cytosol and lumenal sides, respectively. N-terminal residues on the ER lumenal side determine phospholipid headgroup selectivity: swapping them between MBOATs 1, 5, and 7 converts enzyme specificity for different lyso-phospholipids. Finally, the MBOAT7 structure and virtual screening enabled identification of small-molecule inhibitors that may serve as lead compounds for pharmacologic development.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

MeSH terms

Acyltransferases / genetics
Brain Diseases*
Catalysis
Glycerophospholipids
Humans
Kidney Neoplasms*
Membrane Proteins / genetics
Phosphatidylinositols
Phospholipids

Substances

Phosphatidylinositols
Glycerophospholipids
Phospholipids
MBOAT7 protein, human
Acyltransferases
Membrane Proteins

Abstract

Publication types

MeSH terms

Substances

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