TY - JOUR
T1 - Structure and mechanism of human diacylglycerol O-acyltransferase 1
AU - Wang, Lie
AU - Qian, Hongwu
AU - Nian, Yin
AU - Han, Yimo
AU - Ren, Zhenning
AU - Zhang, Hanzhi
AU - Hu, Liya
AU - Prasad, B. V.Venkataram
AU - Laganowsky, Arthur
AU - Yan, Nieng
AU - Zhou, Ming
N1 - Funding Information:
Acknowledgements This work was supported by grants from the NIH (DK122784, HL086392 and GM098878 to M.Z.), the Cancer Prevention and Research Institute of Texas (R1223 to M.Z.), the Robert Welch Foundation (Q1279 to B.V.V.P.), the Ara Parseghian Medical Research Foundation (to N.Y. and Y.H.) and the New Jersey Council for Cancer Research (to H.Q.). N.Y. is supported by the Shirley M. Tilghman endowed professorship from Princeton University. We thank P. Shao for technical support during the acquisition of electron microscope images, and A. Banerjee for advice on the enzymatic assay and purification of αKDH. We acknowledge the use of the Imaging and Analysis Center at Princeton University, which is partially supported by the Princeton Center for Complex Materials, and the National Science Foundation (NSF)-MRSEC program (DMR-1420541).
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/5/21
Y1 - 2020/5/21
N2 - Diacylglycerol O-acyltransferase 1 (DGAT1) synthesizes triacylglycerides and is required for dietary fat absorption and fat storage in humans1. 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 proteins2,3. 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.
AB - Diacylglycerol O-acyltransferase 1 (DGAT1) synthesizes triacylglycerides and is required for dietary fat absorption and fat storage in humans1. 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 proteins2,3. 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.
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U2 - 10.1038/s41586-020-2280-2
DO - 10.1038/s41586-020-2280-2
M3 - Article
C2 - 32433610
AN - SCOPUS:85084440805
SN - 0028-0836
VL - 581
SP - 329
EP - 332
JO - Nature
JF - Nature
IS - 7808
ER -