Cryo-EM structures of the human Elongator complex at work

• Published in: Nature communications Vol. 15; no. 1; pp. 4094 - 16
• Main Authors: Abbassi, Nour-el-Hana, Jaciuk, Marcin, Scherf, David, Böhnert, Pauline, Rau, Alexander, Hammermeister, Alexander, Rawski, Michał, Indyka, Paulina, Wazny, Grzegorz, Chramiec-Głąbik, Andrzej, Dobosz, Dominika, Skupien-Rabian, Bozena, Jankowska, Urszula, Rappsilber, Juri, Schaffrath, Raffael, Lin, Ting-Yu, Glatt, Sebastian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.05.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 101/28; 38/71; 38/90; 631/45/173; 631/45/500; 631/535/1258/1259; 82/80; Acetyl Coenzyme A - chemistry; Acetyl Coenzyme A - metabolism; Acetylation; Anticodons; Cryoelectron Microscopy; Elongated structure; Histone Acetyltransferases - chemistry; Histone Acetyltransferases - genetics; Histone Acetyltransferases - metabolism; Humanities and Social Sciences; Humans; Models, Molecular; Molecular modelling; multidisciplinary; Mutation; Protein Binding; RNA, Transfer - chemistry; RNA, Transfer - genetics; RNA, Transfer - metabolism; Science; Science (multidisciplinary); Structure-function relationships; Transfer RNA; Translation elongation; tRNA; Uridine; Uridine - chemistry; Uridine - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-48251-y

tRNA modifications affect ribosomal elongation speed and co-translational folding dynamics. The Elongator complex is responsible for introducing 5-carboxymethyl at wobble uridine bases (cm 5 U 34 ) in eukaryotic tRNAs. However, the structure and function of human Elongator remain poorly understood. In this study, we present a series of cryo-EM structures of human ELP123 in complex with tRNA and cofactors at four different stages of the reaction. The structures at resolutions of up to 2.9 Å together with complementary functional analyses reveal the molecular mechanism of the modification reaction. Our results show that tRNA binding exposes a universally conserved uridine at position 33 (U 33 ), which triggers acetyl-CoA hydrolysis. We identify a series of conserved residues that are crucial for the radical-based acetylation of U 34 and profile the molecular effects of patient-derived mutations. Together, we provide the high-resolution view of human Elongator and reveal its detailed mechanism of action. Here the authors determined several cryo-EM structures of the human Elongator complex, which modifies anticodons of tRNAs. The structural work is complemented by functional analyses to understand this clinically relevant cellular machine at the molecular level.