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A Leishmania virulence factor harnesses an allosteric kinase switch to regulate its ubiquitin ligase activity

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Leishmania Mexicana

SUBMITTER: Wieland Steinchen

LAB HEAD: Wieland Steinchen

PROVIDER: PXD057190 | Pride | 2025-09-23

REPOSITORIES: Pride

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			Action	DRS
	240202_HX_543_Ba_DeltaN_NoPhos.zip	Other
	240202_HX_543_Ba_DeltaN_Phos.zip	Other
	240202_HX_543_Ba_FL_NoPhos.zip	Other
	240202_HX_543_Ba_FL_Phos.zip	Other
	240202_HX_543_Ba_PLGS.zip	Other

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