PXD034343

PXD034343 is an original dataset announced via ProteomeXchange.

Title	eIF4A1 unwinding activity is RNA sequence-specifically deployed through eIF4A1-multimerisation to facilitate translation of mRNAs with local repressive RNA structure
Description	Oncogenic translational programmes are an emerging hallmark of cancer and often driven by dysregulation of signaling pathways including KRAS and mTORC that converge on the eukaryotic translation initiation (eIF) 4F complex. Altered eIF4F activity promotes translation of oncogene mRNAs that typically contain highly structured 5’UTRs rendering their translation strongly dependent on RNA unwinding by DEAD-box helicase eIF4A1 subunit of the eIF4F complex. In addition, eIF4A1 separately functions to load mRNA into the 43S pre-initiation complex (PIC), an essential step for the translation of cellular mRNA. While eIF4A1-dependent mRNAs have been widely investigated, it is still unclear if highly structured mRNAs recruit and activate eIF4A1 unwinding specifically. Here, we uncover that unwinding by eIF4A1 is activated in an RNA sequence-dependent manner in cells. Our data demonstrate that eIF4A1-dependent mRNAs contain specific RNA sequences, particularly enriched for polypurine-motifs, in their 5’UTR which recruit and specifically stimulate unwinding of local repressive RNA structure by eIF4A1 in an RNA sequence-dependent manner to facilitate translation. Mechanistically, we show that polypurine-rich sequences trigger the formation of RNA sequence-specific multimeric eIF4A1-complexes, assembled of catalytically distinct eIF4A1 subunits, the joint activity of which enhances RNA unwinding activity. Together with our structural data, we describe a model in which conformational changes within eIF4A1 and the RNA through the process of eIF4A1 multimerisation, lead to an optimal interaction of eIF4A1-unwinding subunits with the structured RNA region which enhances unwinding. Hence, we conclude that RNA sequences in addition to protein cofactors contribute to the regulation of cellular eIF4A1 function and promotion of translation of eIF4A1-unwinding dependent mRNAs.
HostingRepository	PRIDE
AnnounceDate	2023-01-17
AnnouncementXML	Submission_2023-01-17_06:09:58.976.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	KellyHodge
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-06-06 02:04:41	ID requested
⏵ 1	2023-01-17 06:09:59	announced

Dataset with its publication pending

submitter keyword: proteomics, TMT,eIF4A1, pulse SILAC

SaraZanivan
contact affiliation	Head of Proteomics, Beatson Institute for Cancer Research
contact email	Sara.Zanivan@glasgow.ac.uk
lab head
KellyHodge
contact affiliation	CRUK Beatson Institute
contact email	k.hodge@beatson.gla.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD034343
     1. Label: PRIDE project
     2. Name: eIF4A1 unwinding activity is RNA sequence-specifically deployed through eIF4A1-multimerisation to facilitate translation of mRNAs with local repressive RNA structure