8QE8

Structure of the non-canonical CTLH E3 substrate receptor WDR26 bound to NMNAT1 substrate

Summary for 8QE8

• Entry DOI: 10.2210/pdb8qe8/pdb
• Related: 8QBN
• EMDB information: 18170 18171 18172 18173 18174 18175 18176 18177 18178 18316 18345
• Descriptor: Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1, WD repeat-containing protein 26, BETA-NICOTINAMIDE RIBOSE MONOPHOSPHATE, ... (4 entities in total)
• Functional Keywords: e3 ubiquitin ligase, ctlh, gid, nmnat1, ypel5, nad, nadh, ligase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 333775.83

Authors

Chrustowicz, J.,Sherpa, D.,Schulman, B.A. (deposition date: 2023-08-30, release date: 2024-05-15, Last modification date: 2025-07-02)

Primary citation

Gottemukkala, K.V.,Chrustowicz, J.,Sherpa, D.,Sepic, S.,Vu, D.T.,Karayel, O.,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

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

PubMed: 38759627
DOI: 10.1016/j.molcel.2024.04.014

Experimental method

ELECTRON MICROSCOPY (3.8 Å)