PXD029455

PXD029455 is an original dataset announced via ProteomeXchange.

Title	MS-based proteomic characterization of Toxoplasma gondii PRP4K and PRP8 interactomes
Description	The apicomplexa comprise a large phylum of single-celled, obligate intracellular protozoa that infect humans and animals and cause severe parasitic diseases. Available therapeutics against these devastating diseases are limited by suboptimal efficacy and frequent side effects, as well as the emergence and spread of resistance. Here, we use a drug repositioning strategy and identify altiratinib, a compound originally developed to treat glioblastoma, as a promising drug candidate with broad spectrum activity against apicomplexans. Altiratinib is parasiticidal and blocks the development of intracellular zoites in the nanomolar range and with a high selectivity index. We have identified TgPRP4K of T. gondii as the primary target of altiratinib by genetic target deconvolution. TgPRP4K is phylogenetically related to the cyclin-dependent-like kinase family (CLK) and its closest ancestor in humans is the splicing factor kinase PRP4 kinase (PRP4K or PRPF4B) and in P. falciparum is PfCLK3 (PF3D7_1114700), a kinase that has been identified as a multistage cross-species antimalarial drug target. We found an altiratinib-resistant parasite line has a wild-type (WT) allele of TgPRP4K and a mutation E1325K in TgPRP8, a protein located in the catalytic core of the spliceosome that has been shown to interact with PRP4K in Schizosaccharomyces pombe to facilitate spliceosome activation. This reinforces the possibility that the PRP4K-PRP8 complex is at the basis for the anti-Toxoplasma activity of altiratinib. To gain insight about the role of both proteins in T. gondii, we characterized their interactomes.
HostingRepository	PRIDE
AnnounceDate	2022-09-01
AnnouncementXML	Submission_2022-09-01_02:58:16.977.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD029455
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Yohann Couté
SpeciesList	scientific name: Toxoplasma gondii; NCBI TaxID: 5811;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2021-11-01 04:59:19	ID requested
⏵ 1	2022-09-01 02:58:18	announced

Swale C, Bellini V, Bowler MW, Flore N, Brenier-Pinchart MP, Cannella D, Belmudes L, Mas C, Cout, é Y, Laurent F, Scherf A, Bougdour A, Hakimi MA, development by selectively targeting a spliceosome kinase. Sci Transl Med, 14(656):eabn3231(2022) [pubmed]

submitter keyword: Toxoplasma gondii, kinase, splicing, interactome, nanoLC-MS/MS

Yohann Couté
contact affiliation	EDyP
contact email	yohann.coute@cea.fr
lab head
Yohann Couté
contact affiliation	EDyP
contact email	yohann.coute@cea.fr
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD029455
     1. Label: PRIDE project
     2. Name: MS-based proteomic characterization of Toxoplasma gondii PRP4K and PRP8 interactomes