Structure and mechanism of human diacylglycerol O-acyltransferase 1

Nature. 2020 May;581(7808):329-332. doi: 10.1038/s41586-020-2280-2.

Lie Wang ^# ¹, Hongwu Qian ^# ², Yin Nian ^# ¹ ³, Yimo Han ^# ² ⁴, Zhenning Ren ¹, Hanzhi Zhang ¹, Liya Hu ¹, B V Venkataram Prasad ¹, Arthur Laganowsky ⁵, Nieng Yan ⁶, Ming Zhou ⁷

Affiliations

1 Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA.
2 Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
3 Ion Channel Research and Drug Development Center, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
4 Department of Material Science and Nanoengineering, Rice University, Houston, TX, USA.
5 Department of Chemistry, Texas A&M University, College Station, TX, USA.
6 Department of Molecular Biology, Princeton University, Princeton, NJ, USA. nyan@princeton.edu.
7 Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA. mzhou@bcm.edu.
# Contributed equally.

PMID: 32433610 DOI: 10.1038/s41586-020-2280-2

Abstract

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 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.

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