Open AccessStructure and mechanism of human diacylglycerol O-acyltransferase 1
Author(s) -
Lie Wang,
HuiFen Qian,
Yin Nian,
Yimo Han,
Zhenning Ren,
Hanzhi Zhang,
Liya Hu,
B. V. Venkataram Prasad,
Arthur Laganowsky,
Nieng Yan,
Ming Zhou
Publication year - 2020
Publication title -
nature
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 15.993
H-Index - 1226
eISSN - 1476-4687
pISSN - 0028-0836
DOI - 10.1038/s41586-020-2280-2
Subject(s) - diacylglycerol kinase , acyltransferase , acyl coa , biochemistry , acyltransferases , chemistry , transmembrane protein , enzyme , transmembrane domain , homotetramer , biophysics , biology , membrane , biosynthesis , gene , protein kinase c , receptor , protein subunit
Diacylglycerol O-acyltransferase 1 (DGAT1) synthesizes triacylglycerides and is required for dietary fat absorption and fat storage in humans 1 . 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 2,3 . 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.