Publication Date
5-1-2020
Journal
Nature
DOI
10.1038/s41586-020-2280-2
PMID
32433610
PMCID
PMC7255049
PubMedCentral® Posted Date
11-13-2020
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Acyl Coenzyme A, Binding Sites, Cryoelectron Microscopy, Diacylglycerol O-Acyltransferase, Diglycerides, Humans, Models, Molecular, Protein Multimerization, Structure-Activity Relationship, Triglycerides
Abstract
Diacylglycerol O-acyltransferase-1 (DGAT1) synthesizes triacylglycerides and is required for dietary fat absorption and fat storage in humans1. DGAT1 belongs to the superfamily of membrane-bound O-acyltransferases (MBOAT) that are found in all kingdoms of life and involved in acylation of lipids and proteins2,3. It remains unclear how human DGAT1 (hDGAT1) or other mammalian members of the MBOAT family recognize their substrates and catalyze their reactions. The absence of three-dimensional structures also hampers rational targeting of hDGAT1 for therapeutic purposes. Here we present the structure of hDGAT1 in complex with a substrate oleoyl Coenzyme A solved by cryo-electron microscopy. Each hDGAT1 protomer has nine transmembrane helices and eight of which form a conserved structural fold that we define as the MBOAT fold. The MBOAT fold in hDGAT1 carves out a hollow chamber in the membrane that encloses highly conserved catalytic residues. The chamber has separate entrances for the two substrates fatty acyl Coenzyme A and diacylglycerol. hDGAT1 can exist as either a homodimer or homotetramer and the two forms have similar enzymatic activity. The N-terminus of hDGAT1 interacts with the neighboring protomer and these interactions are required for the enzymatic activity.
Included in
Biochemistry, Biophysics, and Structural Biology Commons, Biology Commons, Medical Sciences Commons, Medical Specialties Commons
Comments
Associated Data