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- PDB-8p83: Cryo-EM structure of full-length human UBR5 (homotetramer) -

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Basic information

Entry
Database: PDB / ID: 8p83
TitleCryo-EM structure of full-length human UBR5 (homotetramer)
ComponentsE3 ubiquitin-protein ligase UBR5
KeywordsLIGASE / E3 / ubiquitin ligase / HECT
Function / homology
Function and homology information


heterochromatin boundary formation / HECT-type E3 ubiquitin transferase / DNA repair-dependent chromatin remodeling / ubiquitin-ubiquitin ligase activity / progesterone receptor signaling pathway / protein K48-linked ubiquitination / ubiquitin binding / positive regulation of protein import into nucleus / protein polyubiquitination / positive regulation of canonical Wnt signaling pathway ...heterochromatin boundary formation / HECT-type E3 ubiquitin transferase / DNA repair-dependent chromatin remodeling / ubiquitin-ubiquitin ligase activity / progesterone receptor signaling pathway / protein K48-linked ubiquitination / ubiquitin binding / positive regulation of protein import into nucleus / protein polyubiquitination / positive regulation of canonical Wnt signaling pathway / ubiquitin protein ligase activity / DNA repair / DNA damage response / positive regulation of gene expression / perinuclear region of cytoplasm / protein-containing complex / RNA binding / zinc ion binding / nucleoplasm / membrane / nucleus / cytosol / cytoplasm
Similarity search - Function
: / E3 ubiquitin ligase EDD, ubiquitin-associated domain / E3 ubiquitin ligase EDD / Polyadenylate-binding protein/Hyperplastic disc protein / Poly-adenylate binding protein, unique domain / Poly(A)-binding protein C-terminal (PABC) domain profile. / C-terminal domain of Poly(A)-binding protein. Present also in Drosophila hyperplastics discs protein. / PABC (PABP) domain / Zinc finger, UBR-type / Zinc finger UBR-type profile. ...: / E3 ubiquitin ligase EDD, ubiquitin-associated domain / E3 ubiquitin ligase EDD / Polyadenylate-binding protein/Hyperplastic disc protein / Poly-adenylate binding protein, unique domain / Poly(A)-binding protein C-terminal (PABC) domain profile. / C-terminal domain of Poly(A)-binding protein. Present also in Drosophila hyperplastics discs protein. / PABC (PABP) domain / Zinc finger, UBR-type / Zinc finger UBR-type profile. / Putative zinc finger in N-recognin, a recognition component of the N-end rule pathway / Regulator of chromosome condensation 1/beta-lactamase-inhibitor protein II / HECT domain / HECT, E3 ligase catalytic domain / HECT-domain (ubiquitin-transferase) / HECT domain profile. / Domain Homologous to E6-AP Carboxyl Terminus with
Similarity search - Domain/homology
E3 ubiquitin-protein ligase UBR5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.87 Å
AuthorsAguirre, J.D. / Kater, L. / Kempf, G. / Cavadini, S. / Thoma, N.H.
Funding support Switzerland, European Union, 3items
OrganizationGrant numberCountry
Swiss National Science Foundation179541 Switzerland
Swiss National Science Foundation201206 Switzerland
European Research Council (ERC)884331European Union
CitationJournal: Mol Cell / Year: 2023
Title: UBR5 forms ligand-dependent complexes on chromatin to regulate nuclear hormone receptor stability.
Authors: Jonathan M Tsai / Jacob D Aguirre / Yen-Der Li / Jared Brown / Vivian Focht / Lukas Kater / Georg Kempf / Brittany Sandoval / Stefan Schmitt / Justine C Rutter / Pius Galli / Colby R Sandate ...Authors: Jonathan M Tsai / Jacob D Aguirre / Yen-Der Li / Jared Brown / Vivian Focht / Lukas Kater / Georg Kempf / Brittany Sandoval / Stefan Schmitt / Justine C Rutter / Pius Galli / Colby R Sandate / Jevon A Cutler / Charles Zou / Katherine A Donovan / Ryan J Lumpkin / Simone Cavadini / Paul M C Park / Quinlan Sievers / Charlie Hatton / Elizabeth Ener / Brandon D Regalado / Micah T Sperling / Mikołaj Słabicki / Jeonghyeon Kim / Rebecca Zon / Zinan Zhang / Peter G Miller / Roger Belizaire / Adam S Sperling / Eric S Fischer / Rafael Irizarry / Scott A Armstrong / Nicolas H Thomä / Benjamin L Ebert /
Abstract: Nuclear hormone receptors (NRs) are ligand-binding transcription factors that are widely targeted therapeutically. Agonist binding triggers NR activation and subsequent degradation by unknown ligand- ...Nuclear hormone receptors (NRs) are ligand-binding transcription factors that are widely targeted therapeutically. Agonist binding triggers NR activation and subsequent degradation by unknown ligand-dependent ubiquitin ligase machinery. NR degradation is critical for therapeutic efficacy in malignancies that are driven by retinoic acid and estrogen receptors. Here, we demonstrate the ubiquitin ligase UBR5 drives degradation of multiple agonist-bound NRs, including the retinoic acid receptor alpha (RARA), retinoid x receptor alpha (RXRA), glucocorticoid, estrogen, liver-X, progesterone, and vitamin D receptors. We present the high-resolution cryo-EMstructure of full-length human UBR5 and a negative stain model representing its interaction with RARA/RXRA. Agonist ligands induce sequential, mutually exclusive recruitment of nuclear coactivators (NCOAs) and UBR5 to chromatin to regulate transcriptional networks. Other pharmacological ligands such as selective estrogen receptor degraders (SERDs) degrade their receptors through differential recruitment of UBR5 or RNF111. We establish the UBR5 transcriptional regulatory hub as a common mediator and regulator of NR-induced transcription.
History
DepositionMay 31, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 14, 2023Provider: repository / Type: Initial release
Revision 1.1Aug 2, 2023Group: 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.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Aug 16, 2023Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / citation / Item: _citation.journal_volume / _citation.page_first

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: E3 ubiquitin-protein ligase UBR5
B: E3 ubiquitin-protein ligase UBR5
C: E3 ubiquitin-protein ligase UBR5
D: E3 ubiquitin-protein ligase UBR5


Theoretical massNumber of molelcules
Total (without water)1,253,0554
Polymers1,253,0554
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
E3 ubiquitin-protein ligase UBR5 / E3 ubiquitin-protein ligase / HECT domain-containing 1 / HECT-type E3 ubiquitin transferase UBR5 / ...E3 ubiquitin-protein ligase / HECT domain-containing 1 / HECT-type E3 ubiquitin transferase UBR5 / Hyperplastic discs protein homolog / hHYD / Progestin-induced protein


Mass: 313263.688 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: UBR5, EDD, EDD1, HYD, KIAA0896 / Cell line (production host): HEK293 / Production host: Homo sapiens (human)
References: UniProt: O95071, HECT-type E3 ubiquitin transferase

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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: Tetramer of UBR5 / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.6
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
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: 2200 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameCategory
7Cootmodel fitting
8ISOLDEmodel fitting
14Rosettamodel refinement
15PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.87 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 393327 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL

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