Structure and mechanism of human diacylglycerol O-acyltransferase 1
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Abstract
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.
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Within the binding pocket of DGAT2, residues Glu243 and His163 are analogous to the proposed catalytic residues in DGAT1 (His415 and Glu416).
“Within the binding pocket of DGAT2, we identified residues (Glu243 and His163) (Fig. 3b) that are analogous to the proposed catalytic residues in DGAT1 (His415 and Glu416)51, although we note that the nearby Ser244 in DGAT2 may present an alternative mechanism through an acyl-enzyme intermediate.”
From Highly accurate protein structure prediction for the human proteome (2021) · cites this paper as [51]
The mechanism of PSS1 bears resemblance to previously proposed mechanisms of MBOATs.
“Intriguingly, the mechanism of PSS1 bears resemblance to the previously proposed mechanisms of membrane-bound O-acyl transferases (MBOATs)42–48”
From Molecular insights into human phosphatidylserine synthase 1 reveal its inhibition promotes LDL uptake (2024) · cites this paper as [44]
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References 70 · Cited by 123
- Authors
- Wang, L., Qian, H., Nian, Y., Han, Y., Ren, Z., Zhang, H., Hu, L., Prasad, B. V. V., Laganowsky, A., Yan, N., & Zhou, M.
- Affiliations
- Baylor College of Medicine (US)
- Princeton University (US)
- Texas A&M University (US)
- Corresponding author
- Yan, Nieng
- Zhou, Ming
- ORCID
- Venue
- Nature
- Published
- 2020-05-13
- Volume
- 581
- Issue
- 7808
- Pages
- 329-332
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7255049
- OpenAlex
- W3024565489
- Cited by
- 123
- References
- 70
- Citations by year
- 2026: 12 · 2025: 23 · 2024: 17 · 2023: 23 · 2022: 20 · 2021: 23 · 2020: 5
- FWCI
- 7.59
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Cancer Prevention and Research Institute of Texas (R1223)
- Princeton University
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL086392)
- National Institute of General Medical Sciences (R01GM098878)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK122784, R01DK088057)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- diacylglycerol O-acyltransferase 1, DGAT1, triglyceride synthesis, oleoyl-CoA, diacylglycerol, membrane protein structure, transmembrane helices, homodimer, homotetramer, substrate recognition, enzyme mechanism, dietary fat absorption, fat deposition
- MeSH terms
- Acyl Coenzyme A, Binding Sites, Diglycerides, Humans, Models, Molecular, Structure-Activity Relationship, Triglycerides, Cryoelectron Microscopy, Diacylglycerol O-Acyltransferase, Protein Multimerization
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