8E50

Cryo-EM structure of human glycerol-3-phosphate acyltransferase 1 (GPAT1) in complex with CoA and palmitoyl-LPA

8E50 の概要

• エントリーDOI: 10.2210/pdb8e50/pdb
• 関連するPDBエントリー: 8E4Y
• EMDBエントリー: 27898 27899
• 分子名称: Glycerol-3-phosphate acyltransferase 1, mitochondrial, COENZYME A, (2R)-2-hydroxy-3-(phosphonooxy)propyl hexadecanoate (3 entities in total)
• 機能のキーワード: acyltransferase, lpa, monotopic, mitochondrial, membrane protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 88097.49

構造登録者

Wasilko, D.J.,Johnson, Z.L.,Ammirati, M.,Chang, J.S.,Han, S.,Wu, H. (登録日: 2022-08-19, 公開日: 2022-12-21, 最終更新日: 2024-06-19)

主引用文献

Johnson, Z.L.,Ammirati, M.,Wasilko, D.J.,Chang, J.S.,Noell, S.,Foley, T.L.,Yoon, H.,Smith, K.,Asano, S.,Hales, K.,Wan, M.,Yang, Q.,Piotrowski, M.A.,Farley, K.A.,Gilbert, T.,Aschenbrenner, L.M.,Fennell, K.F.,Dutra, J.K.,Xu, M.,Guo, C.,Varghese, A.E.,Bellenger, J.,Quinn, A.,Am Ende, C.W.,West, G.M.,Griffor, M.C.,Bennett, D.,Calabrese, M.,Steppan, C.M.,Han, S.,Wu, H.
Structural basis of the acyl-transfer mechanism of human GPAT1.
Nat.Struct.Mol.Biol., 30:22-30, 2023

PubMed Abstract: Glycerol-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.

PubMed: 36522428
DOI: 10.1038/s41594-022-00884-7

実験手法

ELECTRON MICROSCOPY (3.67 Å)