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Gottemukkala, K.V.* ; Chrustowicz, J.* ; Sherpa, D.* ; Sepic, S.* ; Vu, D.T.* ; Karayel, Ö.* ; Papadopoulou, E.C.* ; Gross, A.* ; Schorpp, K. ; von Gronau, S.* ; Hadian, K. ; Murray, P.J.* ; Mann, M.* ; Schulman, B.A.* ; Alpi, A.F.*

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

Mol. Cell 84, 1948-1963.e11 (2024)

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	Open Access Gold (Paid Option)

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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-WDR26-CTLH E3 acts as a modulator of NMNAT1-dependent metabolism.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Ctlh E3 Ligase ; Nmnat1 ; Wdr26 ; Ypel5 ; Degron Mimicry ; Internal Degron ; Metabolic Enzyme ; Prodrug Metabolism ; Ubiquitin Proteasome System ; Ubiquitylation; Nicotinamide Mononucleotide Adenylyltransferase; Ubiquitin-proteasome System; Protein; Nad(+); Mechanism; Muskelin; Reveals; Complex; Binding; Cullin

ISSN (print) / ISBN 1097-2765

e-ISSN 1097-4164

Journal Molecular Cell

Quellenangaben Volume: 84, Issue: 10, Pages: 1948-1963.e11

Publisher Elsevier

Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Research Unit Signaling and Translation (SAT)

Grants European Union (HORIZON EUROPE European Research Council, UPSmeetMet)
Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)
Max Planck Society for Advanced Sciences