2. Academic Validation
  3. Structure and catalytic mechanism of a human triacylglycerol-synthesis enzyme

Structure and catalytic mechanism of a human triacylglycerol-synthesis enzyme

  • Nature. 2020 May;581(7808):323-328. doi: 10.1038/s41586-020-2289-6.
Xuewu Sui 1 2,  Kun Wang 1 2,  Nina L Gluchowski 1 2 3,  Shane D Elliott 1 2,  Maofu Liao # 4,  Tobias C Walther # 5 6 7 8,  Robert V Farese Jr # 9 10 11
Affiliations

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 Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, MA, USA.
  • 4 Department of Cell Biology, Harvard Medical School, Boston, MA, USA. [email protected].
  • 5 Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Boston, MA, USA. [email protected].
  • 6 Department of Cell Biology, Harvard Medical School, Boston, MA, USA. [email protected].
  • 7 Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
  • 8 Howard Hughes Medical Institute, Boston, MA, USA. [email protected].
  • 9 Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Boston, MA, USA. [email protected].
  • 10 Department of Cell Biology, Harvard Medical School, Boston, MA, USA. [email protected].
  • 11 Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
  • # Contributed equally.
PMID: 32433611 DOI: 10.1038/s41586-020-2289-6
Abstract

Triacylglycerols store metabolic energy in organisms and have industrial uses as foods and fuels. Excessive accumulation of triacylglycerols in humans causes obesity and is associated with metabolic diseases1. Triacylglycerol synthesis is catalysed by acyl-CoA diacylglycerol Acyltransferase (DGAT) enzymes2-4, the structures and catalytic mechanisms of which remain unknown. Here we determined the structure of dimeric human DGAT1, a member of the membrane-bound O-acyltransferase (MBOAT) family, by cryo-electron microscopy at approximately 3.0 Å resolution. DGAT1 forms a homodimer through N-terminal segments and a hydrophobic interface, with putative active sites within the membrane region. A structure obtained with oleoyl-CoA substrate resolved at approximately 3.2 Å shows that the CoA moiety binds DGAT1 on the cytosolic side and the acyl group lies deep within a hydrophobic channel, positioning the acyl-CoA thioester bond near an invariant catalytic histidine residue. The reaction centre is located inside a large cavity, which opens laterally to the membrane bilayer, providing lipid access to the active site. A lipid-like density-possibly representing an acyl-acceptor molecule-is located within the reaction centre, orthogonal to acyl-CoA. Insights provided by the DGAT1 structures, together with mutagenesis and functional studies, provide the basis for a model of the catalysis of triacylglycerol synthesis by DGAT.

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