EMD-14626

Single-particle
4.32 Å
EMD-14626 Deposition: 26/03/2022
Map released: 15/06/2022
Last modified: 13/12/2023
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-14626

Human elongator Elp456 subcomplex

EMD-14626

Single-particle
4.32 Å
EMD-14626 Deposition: 26/03/2022
Map released: 15/06/2022
Last modified: 13/12/2023
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens
Sample: Elp4, Elp5, Elp6

Deposition Authors: Gaik M , Glatt S
Functional divergence of the two Elongator subcomplexes during neurodevelopment.
PUBMED: 35698786
DOI: doi:10.15252/emmm.202115608
ISSN: 1757-4684
Abstract:
The highly conserved Elongator complex is a translational regulator that plays a critical role in neurodevelopment, neurological diseases, and brain tumors. Numerous clinically relevant variants have been reported in the catalytic Elp123 subcomplex, while no missense mutations in the accessory subcomplex Elp456 have been described. Here, we identify ELP4 and ELP6 variants in patients with developmental delay, epilepsy, intellectual disability, and motor dysfunction. We determine the structures of human and murine Elp456 subcomplexes and locate the mutated residues. We show that patient-derived mutations in Elp456 affect the tRNA modification activity of Elongator in vitro as well as in human and murine cells. Modeling the pathogenic variants in mice recapitulates the clinical features of the patients and reveals neuropathology that differs from the one caused by previously characterized Elp123 mutations. Our study demonstrates a direct correlation between Elp4 and Elp6 mutations, reduced Elongator activity, and neurological defects. Foremost, our data indicate previously unrecognized differences of the Elp123 and Elp456 subcomplexes for individual tRNA species, in different cell types and in different key steps during the neurodevelopment of higher organisms.