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Structure and mechanism of human diacylglycerol O-acyltransferase 1.

<div class='caption-title'>Structure of hDGAT1.</div>
<div class='caption-title'>The reaction chamber and oleoyl-CoA binding site.</div>
<div class='caption-title'>Proposed catalytic mechanism of hDGAT1.</div>
Wang L, Qian H, Nian Y, Han Y, Ren Z, Zhang H, Hu L, Prasad BVV, Laganowsky A, Yan N, Zhou M
OpenAccess logo Nature 581 329-332 (2020)
Cited: 37 times
EuropePMC logo PMID: 32433610

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 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.

Reviews - 6vp0 mentioned but not cited (2)

  1. Update and nomenclature proposal for mammalian lysophospholipid acyltransferases, which create membrane phospholipid diversity. Valentine WJ, Yanagida K, Kawana H, Kono N, Noda NN, Aoki J, Shindou H. J Biol Chem 298 101470 (2022)
  2. A rising tide lifts all MBOATs: recent progress in structural and functional understanding of membrane bound O-acyltransferases. Pierce MR, Hougland JL. Front Physiol 14 1167873 (2023)

Articles - 6vp0 mentioned but not cited (3)

  1. Structure and mechanism of human diacylglycerol O-acyltransferase 1. Wang L, Qian H, Nian Y, Han Y, Ren Z, Zhang H, Hu L, Prasad BVV, Laganowsky A, Yan N, Zhou M. Nature 581 329-332 (2020)
  2. Structure, mechanism, and inhibition of Hedgehog acyltransferase. Coupland CE, Andrei SA, Ansell TB, Carrique L, Kumar P, Sefer L, Schwab RA, Byrne EFX, Pardon E, Steyaert J, Magee AI, Lanyon-Hogg T, Sansom MSP, Tate EW, Siebold C. Mol Cell 81 5025-5038.e10 (2021)
  3. Acyl-CoA-dependent and acyl-CoA-independent avocado acyltransferases positively influence oleic acid content in nonseed triacylglycerols. Behera J, Rahman MM, Shockey J, Kilaru A. Front Plant Sci 13 1056582 (2022)


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  2. Lipid Metabolism in Glioblastoma: From De Novo Synthesis to Storage. Kou Y, Geng F, Guo D. Biomedicines 10 1943 (2022)
  3. Palmitoylation of Hedgehog proteins by Hedgehog acyltransferase: roles in signalling and disease. Resh MD. Open Biol 11 200414 (2021)
  4. Ghrelin octanoylation by ghrelin O-acyltransferase: protein acylation impacting metabolic and neuroendocrine signalling. Davis TR, Pierce MR, Novak SX, Hougland JL. Open Biol 11 210080 (2021)
  5. The genetics of monogenic intestinal epithelial disorders. Babcock SJ, Flores-Marin D, Thiagarajah JR. Hum Genet 142 613-654 (2023)
  6. Mass spectrometry of intact membrane proteins: shifting towards a more native-like context. Oluwole A, Shutin D, Bolla JR. Essays Biochem 67 201-213 (2023)
  7. The (social) lives, deaths, and biophysical phases of lipid droplets. Henne WM. Curr Opin Cell Biol 82 102178 (2023)
  8. Applications of human organoids in the personalized treatment for digestive diseases. Wang Q, Guo F, Jin Y, Ma Y. Signal Transduct Target Ther 7 336 (2022)
  9. Progress of potential drugs targeted in lipid metabolism research. Liang K, Dai JY. Front Pharmacol 13 1067652 (2022)
  10. Lipid droplet biogenesis and functions in health and disease. Zadoorian A, Du X, Yang H. Nat Rev Endocrinol 19 443-459 (2023)

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  1. Highly accurate protein structure prediction for the human proteome. Tunyasuvunakool K, Adler J, Wu Z, Green T, Zielinski M, Žídek A, Bridgland A, Cowie A, Meyer C, Laydon A, Velankar S, Kleywegt GJ, Bateman A, Evans R, Pritzel A, Figurnov M, Ronneberger O, Bates R, Kohl SAA, Potapenko A, Ballard AJ, Romera-Paredes B, Nikolov S, Jain R, Clancy E, Reiman D, Petersen S, Senior AW, Kavukcuoglu K, Birney E, Kohli P, Jumper J, Hassabis D. Nature 596 590-596 (2021)
  2. Substrate and product complexes reveal mechanisms of Hedgehog acylation by HHAT. Jiang Y, Benz TL, Long SB. Science 372 1215-1219 (2021)
  3. The structural basis for the phospholipid remodeling by lysophosphatidylcholine acyltransferase 3. Zhang Q, Yao D, Rao B, Jian L, Chen Y, Hu K, Xia Y, Li S, Shen Y, Qin A, Zhao J, Zhou L, Lei M, Jiang XC, Cao Y. Nat Commun 12 6869 (2021)
  4. Mechanisms and inhibition of Porcupine-mediated Wnt acylation. Liu Y, Qi X, Donnelly L, Elghobashi-Meinhardt N, Long T, Zhou RW, Sun Y, Wang B, Li X. Nature 607 816-822 (2022)
  5. Photochemical Probe Identification of a Small-Molecule Inhibitor Binding Site in Hedgehog Acyltransferase (HHAT)*. Lanyon-Hogg T, Ritzefeld M, Zhang L, Andrei SA, Pogranyi B, Mondal M, Sefer L, Johnston CD, Coupland CE, Greenfield JL, Newington J, Fuchter MJ, Magee AI, Siebold C, Tate EW. Angew Chem Int Ed Engl 60 13542-13547 (2021)
  6. Physical Characterization of Triolein and Implications for Its Role in Lipid Droplet Biogenesis. Kim S, Voth GA. J Phys Chem B 125 6874-6888 (2021)
  7. HProteome-BSite: predicted binding sites and ligands in human 3D proteome. Sim J, Kwon S, Seok C. Nucleic Acids Res 51 D403-D408 (2023)
  8. Characterization of a Haematococcus pluvialis Diacylglycerol Acyltransferase 1 and Its Potential in Unsaturated Fatty Acid-Rich Triacylglycerol Production. Cui H, Xu W, Zhu X, Zhao C, Cui Y, Ji C, Zhang C, Xue J, Qin S, Jia X, Li R. Front Plant Sci 12 771300 (2021)
  9. Hedgehog acyltransferase catalyzes a random sequential reaction and utilizes multiple fatty acyl-CoA substrates. Schonbrun AR, Resh MD. J Biol Chem 298 102422 (2022)
  10. The structure of phosphatidylinositol remodeling MBOAT7 reveals its catalytic mechanism and enables inhibitor identification. Wang K, Lee CW, Sui X, Kim S, Wang S, Higgs AB, Baublis AJ, Voth GA, Liao M, Walther TC, Farese RV. Nat Commun 14 3533 (2023)
  11. Kinetic Characterization and Catalytic Mechanism of N-Acetylornithine Aminotransferase Encoded by slr1022 Gene from Synechocystis sp. PCC6803. Li ZM, Bai F, Wang X, Xie C, Wan Y, Li Y, Liu J, Li Z. Int J Mol Sci 24 5853 (2023)
  12. Oral IRAK4 inhibitor BAY-1834845 prevents acute respiratory distress syndrome. Li Q, Li R, Yin H, Wang S, Liu B, Li J, Zhou M, Yan Q, Lu L. Biomed Pharmacother 153 113459 (2022)
  13. Structure of a eukaryotic cholinephosphotransferase-1 reveals mechanisms of substrate recognition and catalysis. Wang L, Zhou M. Nat Commun 14 2753 (2023)
  14. Cellular Uptake of a Fluorescent Ligand Reveals Ghrelin O-Acyltransferase Interacts with Extracellular Peptides and Exhibits Unexpected Localization for a Secretory Pathway Enzyme. Campaña MB, Davis TR, Novak SX, Cleverdon ER, Bates M, Krishnan N, Curtis ER, Childs MD, Pierce MR, Morales-Rodriguez Y, Sieburg MA, Hehnly H, Luyt LG, Hougland JL. ACS Chem Biol 18 1880-1890 (2023)
  15. Discovery of novel DGAT1 inhibitors by combination of machine learning methods, pharmacophore model and 3D-QSAR model. Zhang H, Shen C, Zhang HR, Chen WX, Luo QQ, Ding L. Mol Divers 25 1481-1495 (2021)
  16. Identification of an alternative triglyceride biosynthesis pathway. McLelland GL, Lopez-Osias M, Verzijl CRC, Ellenbroek BD, Oliveira RA, Boon NJ, Dekker M, van den Hengel LG, Ali R, Janssen H, Song JY, Krimpenfort P, van Zutphen T, Jonker JW, Brummelkamp TR. Nature 621 171-178 (2023)
  17. Mechanism of D-alanine transfer to teichoic acids shows how bacteria acylate cell envelope polymers. Schultz BJ, Snow ED, Walker S. Nat Microbiol 8 1318-1329 (2023)
  18. Mechanism of action for small-molecule inhibitors of triacylglycerol synthesis. Sui X, Wang K, Song K, Xu C, Song J, Lee CW, Liao M, Farese RV, Walther TC. Nat Commun 14 3100 (2023)
  19. Nanodisc scaffold peptide (NSPr) replaces detergent by reconstituting acyl-CoA:cholesterol acyltransferase 1 into peptidiscs. Neumann B, Chao K, Chang CCY, Chang TY. Arch Biochem Biophys 691 108518 (2020)
  20. Quzhi Formula Alleviates Nonalcoholic Steatohepatitis by Impairing Hepatocyte Lipid Accumulation and Inflammation via Bip/eIF2α Signaling. Wu YL, Wu JX, Shen TT, Chai HS, Chen HF, Zhang Q. J Clin Transl Hepatol 10 1050-1058 (2022)
  21. Saccharomyces cerevisiae Δ9-desaturase Ole1 forms a supercomplex with Slc1 and Dga1. Greenwood BL, Luo Z, Ahmed T, Huang D, Stuart DT. J Biol Chem 299 104882 (2023)
  22. WssI from the Gram-negative bacterial cellulose synthase is an O-acetyltransferase that acts on cello-oligomers with several acetyl donor substrates. Burnett AJN, Rodriguez E, Constable S, Lowrance B, Fish M, Weadge JT. J Biol Chem 299 104849 (2023)


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