Non-canonical substrate recognition by the human WDR26-CTLH E3 ligase regulates 
prodrug metabolism

Gottemukkala, Karthik V.; Chrustowicz, Jakub; Sherpa, Dawafuti; Sepic, Sara; Tung Vu, Duc; Karayel, Ozge; Papadopoulou, Eleftheria C.; Gross, Annette; Schorpp, Kenji; von Gronau, Susanne; Hadian, Kamyar; Murray, Peter J.; Mann, Matthias; Schulman, Brenda A.; Alpi, Arno F.

doi:10.1016/j.molcel.2024.04.014

Item

ITEM ACTIONSEXPORT

Add to Basket

Local TagsRelease HistoryDetailsSummary

Released

Journal Article

Non-canonical substrate recognition by the human WDR26-CTLH E3 ligase regulates prodrug metabolism

MPS-Authors

/persons/resource/persons262701

Gottemukkala, Karthik V.
Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons245081

Chrustowicz, Jakub
Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons238966

Sherpa, Dawafuti
Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons300125

Sepic, Sara
Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons275352

Tung Vu, Duc
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons213408

Karayel, Ozge
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons297415

Papadopoulou, Eleftheria C.
Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons298067

Gross, Annette
Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society;
Murray, Peter / Immunoregulation, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons78034

von Gronau, Susanne
Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons215416

Murray, Peter J.
Murray, Peter / Immunoregulation, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons78356

Mann, Matthias
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons213292

Schulman, Brenda A.
Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons77672

Alpi, Arno F.
Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society;

External Resource

No external resources are shared

Fulltext (restricted access)

There are currently no full texts shared for your IP range.

Fulltext (public)

There are no public fulltexts stored in PuRe

Supplementary Material (public)

There is no public supplementary material available

Citation

Gottemukkala, K. V., Chrustowicz, J., Sherpa, D., Sepic, S., Tung Vu, D., Karayel, O., et al. (2024). Non-canonical substrate recognition by the human WDR26-CTLH E3 ligase regulates prodrug metabolism. Molecular Cell, 84(10), 1948-1963.e11. doi:10.1016/j.molcel.2024.04.014.

Cite as: https://hdl.handle.net/21.11116/0000-000F-D5FD-4

Abstract

The yeast glucose-induced degradation-deficient (GID) E3 ubiquitin ligase forms a suite of complexes with interchangeable receptors that selectively recruit N-terminal degron motifs of metabolic enzyme substrates. The orthologous higher eukaryotic C-terminal to LisH (CTLH) E3 complex has been proposed to also recognize substrates through an alternative subunit, WDR26, which promotes the formation of supramolecular CTLH E3 assemblies. Here, we discover that human WDR26 binds the metabolic enzyme nicotinamide/nicotinic-acid-mononucleotide-adenylyltransferase 1 (NMNAT1) and mediates its CTLH E3-dependent ubiquitylation independently of canonical GID/CTLH E3-family substrate receptors. The CTLH subunit YPEL5 inhibits NMNAT1 ubiquitylation and cellular turnover by WDR26-CTLH E3, thereby affecting NMNAT1-mediated metabolic activation and cytotoxicity of the prodrug tiazofurin. Cryoelectron microscopy (cryo-EM) structures of NMNAT1- and YPEL5-bound WDR26-CTLH E3 complexes reveal an internal basic degron motif of NMNAT1 essential for targeting by WDR26-CTLH E3 and degron mimicry by YPEL5's N terminus antagonizing substrate binding. Thus, our data provide a mechanistic understanding of how YPEL5-WDR26CTLH E3 acts as a modulator of NMNAT1-dependent metabolism.