2025-10-16 マックス・プランク研究所
Leishmania parasites require the protein TKUL to maintain infections of host cells. This protein combines two enzymatic activities in a single molecule. If the TKUL kinase domain (yellow) is blocked with an inhibitor, it can no longer activate the ubiquitin ligase domain (blue).
© MPI f. Multidisciplinary Sciences/ Johannes Pauly, Sonja Lorenz
<関連情報>
- https://www.mpg.de/25560572/new-druggable-protein-discovered-in-leishmania-parasites
- https://www.cell.com/molecular-cell/fulltext/S1097-2765(25)00743-9
リーシュマニアの毒性因子は、アロステリックキナーゼスイッチを利用してユビキチンリガーゼ活性を制御する A Leishmania virulence factor harnesses an allosteric kinase switch to regulate its ubiquitin ligase activity
Thornton J. Fokkens ∙ Elisa T. Rauh ∙ Madita Wolter ∙ … ∙ Ulrike Schleicher ∙ Christian J. Janzen ∙ Sonja Lorenz
Molecular Cell Published: September 24, 2025
DOI:https://doi.org/10.1016/j.molcel.2025.09.002
Highlights
- A kinase-ubiquitin ligase domain module is seen in different unicellular eukaryotes
- L. mexicana TKUL requires this dual-functional module during macrophage infections
- TKUL’s ligase activity requires the kinase activity, enabling allosteric inhibition
- TKUL employs L. mexicana HSP70 as an adaptor to ubiquitylate unfolded substrates
Summary
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, tetratricopeptide repeat (TPR)-kinase-ubiquitin ligase (TKUL), is essential for L. mexicana to sustain macrophage infections and that TKUL can cooperate with parasite heat shock protein 70 (HSP70) to modify unfolded proteins with degradative ubiquitin chains. Intriguingly, the homologous to E6AP C-terminus (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.
