Structure and mechanism of human diacylglycerol O-acyltransferase 1.

TitleStructure and mechanism of human diacylglycerol O-acyltransferase 1.
Publication TypeJournal Article
Year of Publication2020
AuthorsWang, L, Qian, H, Nian, Y, Han, Y, Ren, Z, Zhang, H, Hu, L, Prasad, BVVenkatar, Laganowsky, A, Yan, N, Zhou, M
Date Published2020 May
KeywordsAcyl Coenzyme A, Binding Sites, Cryoelectron Microscopy, Diacylglycerol O-Acyltransferase, Diglycerides, Humans, Models, Molecular, Protein Multimerization, Structure-Activity Relationship, Triglycerides

<p>Diacylglycerol O-acyltransferase 1 (DGAT1) synthesizes triacylglycerides and is required for dietary fat absorption and fat storage in humans. DGAT1 belongs to the membrane-bound O-acyltransferase (MBOAT) superfamily, members of which are found in all kingdoms of life and are involved in the acylation of lipids and proteins. How human DGAT1 and other mammalian members of the MBOAT family recognize their substrates and catalyse their reactions is unknown. The absence of three-dimensional structures also hampers rational targeting of DGAT1 for therapeutic purposes. Here we present the cryo-electron microscopy structure of human DGAT1 in complex with an oleoyl-CoA substrate. Each DGAT1 protomer has nine transmembrane helices, eight of which form a conserved structural fold that we name the MBOAT fold. The MBOAT fold in DGAT1 forms a hollow chamber in the membrane that encloses highly conserved catalytic residues. The chamber has separate entrances for each of the two substrates, fatty acyl-CoA and diacylglycerol. DGAT1 can exist as either a homodimer or a homotetramer and the two forms have similar enzymatic activity. The N terminus of DGAT1 interacts with the neighbouring protomer and these interactions are required for enzymatic activity.</p>

Alternate JournalNature
PubMed ID32433610
PubMed Central IDPMC7255049
Grant ListR01 DK088057 / DK / NIDDK NIH HHS / United States
R01 DK122784 / DK / NIDDK NIH HHS / United States
R01 GM098878 / GM / NIGMS NIH HHS / United States
R01 HL086392 / HL / NHLBI NIH HHS / United States