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TitleNon-canonical substrate recognition by the human WDR26-CTLH E3 ligase regulates prodrug metabolism.
Journal, issue, pagesMol Cell, Vol. 84, Issue 10, Page 1948-1963.e11, Year 2024
Publish dateMay 16, 2024
AuthorsKarthik V Gottemukkala / Jakub Chrustowicz / Dawafuti Sherpa / Sara Sepic / Duc Tung Vu / Özge Karayel / Eleftheria C Papadopoulou / Annette Gross / Kenji Schorpp / Susanne von Gronau / Kamyar Hadian / Peter J Murray / Matthias Mann / Brenda A Schulman / Arno F Alpi /
PubMed AbstractThe 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 ...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.
External linksMol Cell / PubMed:38759627
MethodsEM (single particle)
Resolution3.2 - 13.9 Å
Structure data

EMDB-18170: YPEL5-bound WDR26-CTLH E3 ligase - assembly I
Method: EM (single particle) / Resolution: 8.9 Å

EMDB-18171: YPEL5-bound WDR26-CTLH E3 ligase - assembly II
Method: EM (single particle) / Resolution: 11.2 Å

EMDB-18172: NMNAT1 core-bound RANBP9-TWA1-WDR26 module of WDR26-CTLH E3 ligase
Method: EM (single particle) / Resolution: 4.7 Å

EMDB-18173: NMNAT1 loop-bound RANBP9-TWA1-WDR26 module of WDR26-CTLH E3 ligase
Method: EM (single particle) / Resolution: 8.7 Å

EMDB-18174: NMNAT1-bound WDR26-CTLH E3 ligase assembly I - class 1
Method: EM (single particle) / Resolution: 10.0 Å

EMDB-18175: NMNAT1-bound WDR26-CTLH E3 ligase assembly I - class 2
Method: EM (single particle) / Resolution: 10.3 Å

EMDB-18176: NMNAT1-bound WDR26-CTLH E3 ligase assembly II - class 1
Method: EM (single particle) / Resolution: 11.5 Å

EMDB-18177: NMNAT1-bound WDR26-CTLH E3 ligase assembly II - class 2
Method: EM (single particle) / Resolution: 13.9 Å

EMDB-18178: NMNAT1-bound WDR26-CTLH E3 ligase assembly II - class 3
Method: EM (single particle) / Resolution: 12.2 Å

18316

8qbn

EMDB-18316, PDB-8qbn:
Structure of the non-canonical CTLH E3 substrate receptor WDR26 bound to YPEL5
Method: EM (single particle) / Resolution: 3.2 Å

18345

8qe8

EMDB-18345, PDB-8qe8:
Structure of the non-canonical CTLH E3 substrate receptor WDR26 bound to NMNAT1 substrate
Method: EM (single particle) / Resolution: 3.8 Å

Chemicals

ChemComp-ZN:
Unknown entry

ChemComp-NMN:
BETA-NICOTINAMIDE RIBOSE MONOPHOSPHATE / Nicotinamide mononucleotide

Source
  • homo sapiens (human)
KeywordsLIGASE / E3 ubiquitin ligase / CTLH / GID / NMNAT1 / YPEL5 / NAD / NADH

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