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Cryo-EM structure of human glycerol-3-phosphate acyltransferase 1 (GPAT1) in complex with 2-oxohexadecyl-CoA
Structural highlights
FunctionGPAT1_HUMAN Esterifies acyl-group from acyl-ACP to the sn-1 position of glycerol-3-phosphate, an essential step in glycerolipids biosynthesis such as triglycerides, phosphatidic acids and lysophosphatidic acids.[1] Publication Abstract from PubMedGlycerol-3-phosphate acyltransferase (GPAT)1 is a mitochondrial outer membrane protein that catalyzes the first step of de novo glycerolipid biosynthesis. Hepatic expression of GPAT1 is linked to liver fat accumulation and the severity of nonalcoholic fatty liver diseases. Here we present the cryo-EM structures of human GPAT1 in substrate analog-bound and product-bound states. The structures reveal an N-terminal acyltransferase domain that harbors important catalytic motifs and a tightly associated C-terminal domain that is critical for proper protein folding. Unexpectedly, GPAT1 has no transmembrane regions as previously proposed but instead associates with the membrane via an amphipathic surface patch and an N-terminal loop-helix region that contains a mitochondrial-targeting signal. Combined structural, computational and functional studies uncover a hydrophobic pathway within GPAT1 for lipid trafficking. The results presented herein lay a framework for rational inhibitor development for GPAT1. Structural basis of the acyl-transfer mechanism of human GPAT1.,Johnson ZL, Ammirati M, Wasilko DJ, Chang JS, Noell S, Foley TL, Yoon H, Smith K, Asano S, Hales K, Wan M, Yang Q, Piotrowski MA, Farley KA, Gilbert T, Aschenbrenner LM, Fennell KF, Dutra JK, Xu M, Guo C, Varghese AE, Bellenger J, Quinn A, Am Ende CW, West GM, Griffor MC, Bennett D, Calabrese M, Steppan CM, Han S, Wu H Nat Struct Mol Biol. 2023 Jan;30(1):22-30. doi: 10.1038/s41594-022-00884-7. Epub , 2022 Dec 15. PMID:36522428[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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