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- PDB-8qe8: Structure of the non-canonical CTLH E3 substrate receptor WDR26 b... -

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Basic information

Entry
Database: PDB / ID: 8qe8
TitleStructure of the non-canonical CTLH E3 substrate receptor WDR26 bound to NMNAT1 substrate
Components
  • Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1
  • WD repeat-containing protein 26
KeywordsLIGASE / E3 ubiquitin ligase / CTLH / GID / NMNAT1 / YPEL5 / NAD / NADH
Function / homology
Function and homology information


negative regulation of apoptotic DNA fragmentation / protein ADP-ribosyltransferase-substrate adaptor activity / GID complex / nicotinamide-nucleotide adenylyltransferase / nicotinate-nucleotide adenylyltransferase / nicotinamide-nucleotide adenylyltransferase activity / nucleotide biosynthetic process / nicotinate-nucleotide adenylyltransferase activity / Nicotinate metabolism / ATP generation from poly-ADP-D-ribose ...negative regulation of apoptotic DNA fragmentation / protein ADP-ribosyltransferase-substrate adaptor activity / GID complex / nicotinamide-nucleotide adenylyltransferase / nicotinate-nucleotide adenylyltransferase / nicotinamide-nucleotide adenylyltransferase activity / nucleotide biosynthetic process / nicotinate-nucleotide adenylyltransferase activity / Nicotinate metabolism / ATP generation from poly-ADP-D-ribose / NAD biosynthetic process / ubiquitin ligase complex / response to wounding / proteasome-mediated ubiquitin-dependent protein catabolic process / negative regulation of neuron apoptotic process / positive regulation of MAPK cascade / nuclear body / negative regulation of DNA-templated transcription / chromatin / mitochondrion / nucleoplasm / ATP binding / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Nicotinamide/nicotinate mononucleotide adenylyltransferase, eukaryotic / LisH-like dimerisation domain / Nicotinate/nicotinamide nucleotide adenylyltransferase / C-terminal to LisH motif. / CTLH, C-terminal LisH motif / C-terminal to LisH (CTLH) motif profile. / LIS1 homology (LisH) motif profile. / LIS1 homology motif / Cytidylyltransferase-like / Cytidyltransferase-like domain ...Nicotinamide/nicotinate mononucleotide adenylyltransferase, eukaryotic / LisH-like dimerisation domain / Nicotinate/nicotinamide nucleotide adenylyltransferase / C-terminal to LisH motif. / CTLH, C-terminal LisH motif / C-terminal to LisH (CTLH) motif profile. / LIS1 homology (LisH) motif profile. / LIS1 homology motif / Cytidylyltransferase-like / Cytidyltransferase-like domain / Rossmann-like alpha/beta/alpha sandwich fold / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
BETA-NICOTINAMIDE RIBOSE MONOPHOSPHATE / WD repeat-containing protein 26 / Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsChrustowicz, J. / Sherpa, D. / Schulman, B.A.
Funding support Germany, European Union, 3items
OrganizationGrant numberCountry
Max Planck Society Germany
European Research Council (ERC)UPSmeetMet, 101098161European Union
German Research Foundation (DFG)SCHU 3196/1-1 Germany
CitationJournal: Mol Cell / Year: 2024
Title: Non-canonical substrate recognition by the human WDR26-CTLH E3 ligase regulates prodrug metabolism.
Authors: Karthik V Gottemukkala / Jakub Chrustowicz / Dawafuti Sherpa / Sara Sepic / Duc Tung Vu / Özge Karayel / Eleftheria C Papadopoulou / Annette Gross / Kenji Schorpp / Susanne von Gronau / ...Authors: Karthik 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 /
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 ...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.
History
DepositionAug 30, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 15, 2024Provider: repository / Type: Initial release
Revision 1.1May 29, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
4: Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1
5: Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1
6: Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1
A: WD repeat-containing protein 26
3: Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1
2: Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1
1: Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1
B: WD repeat-containing protein 26
hetero molecules


Theoretical massNumber of molelcules
Total (without water)333,77612
Polymers332,9758
Non-polymers8014
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein
Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1


Mass: 31982.502 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NMNAT1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9HAN9
#2: Protein WD repeat-containing protein 26 / CUL4- and DDB1-associated WDR protein 2 / Myocardial ischemic preconditioning up-regulated protein 2


Mass: 70539.773 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WDR26, CDW2, MIP2, PRO0852 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9H7D7
#3: Chemical ChemComp-NMN / BETA-NICOTINAMIDE RIBOSE MONOPHOSPHATE / NICOTINAMIDE MONONUCLEOTIDE / Nicotinamide mononucleotide


Mass: 335.227 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C11H16N2O8P / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Complex of human WDR26-CTLH E3 ligase bound to NMNAT1 / Type: COMPLEX
Details: Map obtained by focused refinement over NMNAT1-bound WDR26 dimer
Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightValue: 1.1 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: Sample mixed with 0.01% beta-OG right before plunging
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2300 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 71.4 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 5606 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00416150
ELECTRON MICROSCOPYf_angle_d0.56622003
ELECTRON MICROSCOPYf_dihedral_angle_d4.9852230
ELECTRON MICROSCOPYf_chiral_restr0.0452542
ELECTRON MICROSCOPYf_plane_restr0.0042755

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