PXD032925-1

PXD032925 is an original dataset announced via ProteomeXchange.

Title	Distinct roles of the two Elongator subcomplexes during neurodevelopment
Description	The highly conserved Elongator complex is a translational regulator and a subject of growing interest due to its critical role in neurodevelopment, neurological diseases and brain tumors. Clinically relevant mutations have been reported in the catalytic Elp123 subcomplex, while no mutation in the accessory subcomplex Elp456 have been described so far. Here, we identify pathogenic variants of ELP4 and ELP6 in patients with developmental delay, epilepsy as well as intellectual and motor impairment. We use single particle cryo-EM to determine the structures of human and murine Elp456 subcomplexes and reconstitute an active mouse Elongator comprising of all six subunits. We show that patient derived mutations in Elp456 affect the affinity for specific tRNA molecules and diminish the tRNA modification activity of Elongator in vitro as well as in human and murine cells. Modelling the mutations in mice recapitulates the clinical features of the patients and reveals neuropathology that differs from the one caused by previously characterized Elp123 mutations. Altogether, our study demonstrates a direct correlation between Elp4 and Elp6 mutations, reduced Elongator activity and neurological defects. Foremost, our data indicate distinct roles of the Elp123 and Elp456 subcomplexes for different tRNA species, in different cell types and in different key steps during the neurodevelopment of higher organisms.
HostingRepository	PRIDE
AnnounceDate	2022-05-17
AnnouncementXML	Submission_2022-05-17_09:55:23.727.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Ahmed Mohamed
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	TripleTOF 5600

Revision	Datetime	Status	ChangeLog Entry
0	2022-04-02 12:57:04	ID requested
⏵ 1	2022-05-17 09:55:24	announced

Dataset with its publication pending

submitter keyword: Intellectual disability, developmental delay, epilepsy, Fibroblasts, Homo sapiens

Brandon Wainwright
contact affiliation	Lab Head, UQ Diamantina Institute,The University of Queensland
contact email	b.wainwright@imb.uq.edu.au
lab head
Ahmed Mohamed
contact affiliation	Senior Research Officer, WEHI, Parkville, VIC
contact email	mohamed.a@wehi.edu.au
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2022/05/PXD032925

PRIDE project URI

• PRIDE
  1. PXD032925
     1. Label: PRIDE project
     2. Name: Distinct roles of the two Elongator subcomplexes during neurodevelopment