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

Fokkens TJ, Rauh ET, Wolter M, Sebald H, Mitnacht M, Ainatzi S, Sprick S, Teschke L, Eisenhuth N, Huibregtse JM, Butter F, Urlaub H, Karnkowska A, Steinchen W, Schleicher U, Janzen CJ, Lorenz S (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Molecular Cell Elsevier (Cell Press)

Book Volume: 85

Pages Range: 3711-3728.e11

Journal Issue: 19

DOI: 10.1016/j.molcel.2025.09.002

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, 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.

Authors with CRIS profile

Ulrike Schleicher Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene

Involved external institutions

Max-Planck-Institut für Multidisziplinäre Naturwissenschaften / Max Planck Institute for Multidisciplinary Sciences DE Germany (DE) Julius-Maximilians-Universität Würzburg DE Germany (DE) Friedrich-Loeffler-Institut (FLI), Bundesforschungsinstitut für Tiergesundheit DE Germany (DE) University of Texas at Austin US United States (USA) (US) University of Warsaw / Uniwersytet Warszawski PL Poland (PL) Philipps-Universität Marburg DE Germany (DE)

How to cite

APA:

Fokkens, T.J., Rauh, E.T., Wolter, M., Sebald, H., Mitnacht, M., Ainatzi, S.,... Lorenz, S. (2025). A Leishmania virulence factor harnesses an allosteric kinase switch to regulate its ubiquitin ligase activity. Molecular Cell, 85(19), 3711-3728.e11. https://doi.org/10.1016/j.molcel.2025.09.002

MLA:

Fokkens, Thornton J., et al. "A Leishmania virulence factor harnesses an allosteric kinase switch to regulate its ubiquitin ligase activity." Molecular Cell 85.19 (2025): 3711-3728.e11.

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