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- PDB-8ewi: Structure of the human UBR5 HECT-type E3 ubiquitin ligase in a te... -

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Basic information

Entry
Database: PDB / ID: 8ewi
TitleStructure of the human UBR5 HECT-type E3 ubiquitin ligase in a tetrameric form
ComponentsE3 ubiquitin-protein ligase UBR5
KeywordsLIGASE / HECT / E3 ligase
Function / homology
Function and homology information


heterochromatin boundary formation / protein K29-linked ubiquitination / cytoplasm protein quality control by the ubiquitin-proteasome system / nuclear protein quality control by the ubiquitin-proteasome system / protein branched polyubiquitination / HECT-type E3 ubiquitin transferase / cytoplasm protein quality control / protein K11-linked ubiquitination / ubiquitin-ubiquitin ligase activity / DNA repair-dependent chromatin remodeling ...heterochromatin boundary formation / protein K29-linked ubiquitination / cytoplasm protein quality control by the ubiquitin-proteasome system / nuclear protein quality control by the ubiquitin-proteasome system / protein branched polyubiquitination / HECT-type E3 ubiquitin transferase / cytoplasm protein quality control / protein K11-linked ubiquitination / ubiquitin-ubiquitin ligase activity / DNA repair-dependent chromatin remodeling / progesterone receptor signaling pathway / protein K48-linked ubiquitination / ubiquitin binding / negative regulation of smoothened signaling pathway / positive regulation of protein import into nucleus / protein polyubiquitination / ubiquitin protein ligase activity / positive regulation of canonical Wnt signaling pathway / proteasome-mediated ubiquitin-dependent protein catabolic process / DNA repair / DNA damage response / positive regulation of gene expression / chromatin / perinuclear region of cytoplasm / protein-containing complex / RNA binding / zinc ion binding / nucleoplasm / nucleus / membrane / cytoplasm / cytosol
Similarity search - Function
E3 ubiquitin ligase EDD, ubiquitin-associated domain / : / E3 ubiquitin ligase EDD / Poly(A)-binding protein C-terminal (PABC) domain profile. / C-terminal domain of Poly(A)-binding protein. Present also in Drosophila hyperplastics discs protein. / Polyadenylate-binding protein/Hyperplastic disc protein / PABC (PABP) domain / MLLE domain / Zinc finger, UBR-type / Zinc finger UBR-type profile. ...E3 ubiquitin ligase EDD, ubiquitin-associated domain / : / E3 ubiquitin ligase EDD / Poly(A)-binding protein C-terminal (PABC) domain profile. / C-terminal domain of Poly(A)-binding protein. Present also in Drosophila hyperplastics discs protein. / Polyadenylate-binding protein/Hyperplastic disc protein / PABC (PABP) domain / MLLE 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: 3.5 Å
AuthorsWang, F. / He, Q. / Lin, G. / Li, H.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM131754 United States
CitationJournal: Structure / Year: 2023
Title: Structure of the human UBR5 E3 ubiquitin ligase.
Authors: Feng Wang / Qing He / Wenhu Zhan / Ziqi Yu / Efrat Finkin-Groner / Xiaojing Ma / Gang Lin / Huilin Li /
Abstract: The human UBR5 is a single polypeptide chain homology to E6AP C terminus (HECT)-type E3 ubiquitin ligase essential for embryonic development in mammals. Dysregulated UBR5 functions like an ...The human UBR5 is a single polypeptide chain homology to E6AP C terminus (HECT)-type E3 ubiquitin ligase essential for embryonic development in mammals. Dysregulated UBR5 functions like an oncoprotein to promote cancer growth and metastasis. Here, we report that UBR5 assembles into a dimer and a tetramer. Our cryoelectron microscopy (cryo-EM) structures reveal that two crescent-shaped UBR5 monomers assemble head to tail to form the dimer, and two dimers bind face to face to form the cage-like tetramer with all four catalytic HECT domains facing the central cavity. Importantly, the N-terminal region of one subunit and the HECT of the other form an "intermolecular jaw" in the dimer. We show the jaw-lining residues are important for function, suggesting that the intermolecular jaw functions to recruit ubiquitin-loaded E2 to UBR5. Further work is needed to understand how oligomerization regulates UBR5 ligase activity. This work provides a framework for structure-based anticancer drug development and contributes to a growing appreciation of E3 ligase diversity.
History
DepositionOct 23, 2022Deposition site: RCSB / Processing site: RCSB
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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)1,239,67616
Polymers1,238,8914
Non-polymers78512
Water00
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: 309722.750 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
Production host: Insect cell expression vector pTIE1 (others)
References: UniProt: O95071, HECT-type E3 ubiquitin transferase
#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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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: Homodimer of human E3 ligase UBR5 / Type: COMPLEX / Details: UBR5 expressed in insect cell / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.61 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Insect expression vector pBlueBachsGCA1 (others)
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMsodium chlorideNaCl1
225 mM4-(2-hydroxyethyl)-1-piperazineethanesulfonic acidHEPES1
30.5 mMtris(2-carboxyethyl)phosphineTECP1
SpecimenConc.: 0.7 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: freshly purified UBR5
Specimen supportGrid type: Quantifoil R2/1
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 279 K / Details: blot 2S, blot forth 2

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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 FIELD / Nominal magnification: 105000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Temperature (max): 193 K / Temperature (min): 193 K
Image recordingElectron dose: 65 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)
Details: Images were collected in movie-mode at 75 frames per second

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Processing

SoftwareName: PHENIX / Version: 1.20_4459: / Classification: refinement
EM software
IDNameVersionCategory
2cryoSPARC3.2.0image acquisition
4CTFFIND1.4.10CTF correction
9PHENIXmodel refinement
13cryoSPARC3.2.03D reconstruction
CTF correctionType: NONE
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 401469 / Symmetry type: POINT
Atomic model buildingB value: 119 / Protocol: RIGID BODY FIT / Space: REAL / Target criteria: Correlation coefficient
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00356844
ELECTRON MICROSCOPYf_angle_d0.5177040
ELECTRON MICROSCOPYf_dihedral_angle_d12.20221380
ELECTRON MICROSCOPYf_chiral_restr0.0398700
ELECTRON MICROSCOPYf_plane_restr0.0049992

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