PXD057190

PXD057190 is an original dataset announced via ProteomeXchange.

Title	A Leishmania virulence factor harnesses an allosteric kinase switch to regulate its ubiquitin ligase activity
Description	Stringent control of ubiquitylation is a central requirement of signaling specificity in eukaryotes. Here, we discover a domain module integrating protein kinase and ubiquitin ligase domains within a single protein. This module is widespread across unicellular eukaryotic lineages and particularly conserved in Leishmania, the causative agents of major neglected tropical diseases with a strong therapeutic need. We reveal that a gene encoding the module, TKUL, is essential for L. mexicana to sustain macrophage infections and that TKUL can cooperate with HSP70 to modify unfolded proteins with degradative ubiquitin chains. Intriguingly, the HECT-type ubiquitin ligase activity of TKUL requires its atypical kinase domain, with kinase autophosphorylation triggering activating conformational changes across the catalytic module. Consistent with the ligase domain harnessing the kinase domain for regulation, TKUL-driven ubiquitylation can allosterically be suppressed by small-molecule kinase inhibitors. Together, this work establishes an unprecedented allosteric coupling mechanism in the realms of phosphorylation and ubiquitylation.
HostingRepository	PRIDE
AnnounceDate	2025-09-23
AnnouncementXML	Submission_2025-09-23_02:37:18.858.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Wieland Steinchen
SpeciesList	scientific name: Leishmania mexicana; NCBI TaxID: 5665;
ModificationList	No PTMs are included in the dataset
Instrument	Synapt MS

Revision	Datetime	Status	ChangeLog Entry
0	2024-10-25 04:03:46	ID requested
⏵ 1	2025-09-23 02:37:19	announced

Dataset with its publication pending

ProteomeXchange project tag: Hydrogen Deuterium Exchange (HDX-MS)

submitter keyword: Ser/Thr kinase, hydrogen-deuterium exchange mass spectrometry (HDX-MS), enzyme regulation, TPR domain,Ubiquitin ligase, X-ray crystallography, phosphorylation, HECT E3, allostery, heat-shock protein 70 (HSP70)

Wieland Steinchen
contact affiliation	Center for Synthetic Microbiology (SYNMIKRO) & Faculty of Chemistry, Philipps-University Marburg, 35043 Marburg, Germany
contact email	wieland.steinchen@synmikro.uni-marburg.de
lab head
Wieland Steinchen
contact affiliation	Philipps-University Marburg, Department of Chemistry & SYNMIKRO, Karl-von-Frisch-Straße 14, 35043 Marburg, GERMANY
contact email	wieland.steinchen@synmikro.uni-marburg.de
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/2025/09/PXD057190

PRIDE project URI

• PRIDE
  1. PXD057190
     1. Label: PRIDE project
     2. Name: A Leishmania virulence factor harnesses an allosteric kinase switch to regulate its ubiquitin ligase activity