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- PDB-8c07: Structure of HECT E3 UBR5 forming K48 linked Ubiquitin chains -

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Basic information

Entry
Database: PDB / ID: 8c07
TitleStructure of HECT E3 UBR5 forming K48 linked Ubiquitin chains
Components
  • (Polyubiquitin-B) x 2
  • E3 ubiquitin-protein ligase UBR5
KeywordsLIGASE / E3 ligase / UBR5 / Ubiquitination / UBQ / Ubiquitin / HECT / K48 / UBQ-chain / polyubiquitylation
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 / hypothalamus gonadotrophin-releasing hormone neuron development / female meiosis I ...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 / hypothalamus gonadotrophin-releasing hormone neuron development / female meiosis I / positive regulation of protein monoubiquitination / fat pad development / mitochondrion transport along microtubule / ubiquitin-ubiquitin ligase activity / DNA repair-dependent chromatin remodeling / female gonad development / seminiferous tubule development / male meiosis I / positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator / protein K48-linked ubiquitination / progesterone receptor signaling pathway / energy homeostasis / regulation of neuron apoptotic process / regulation of proteasomal protein catabolic process / Maturation of protein E / Maturation of protein E / ER Quality Control Compartment (ERQC) / Myoclonic epilepsy of Lafora / FLT3 signaling by CBL mutants / Prevention of phagosomal-lysosomal fusion / IRAK2 mediated activation of TAK1 complex / Alpha-protein kinase 1 signaling pathway / Glycogen synthesis / IRAK1 recruits IKK complex / IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation / Membrane binding and targetting of GAG proteins / Endosomal Sorting Complex Required For Transport (ESCRT) / Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7 / Negative regulation of FLT3 / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / Constitutive Signaling by NOTCH1 HD Domain Mutants / Regulation of TBK1, IKKε-mediated activation of IRF3, IRF7 upon TLR3 ligation / IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation / NOTCH2 Activation and Transmission of Signal to the Nucleus / TICAM1,TRAF6-dependent induction of TAK1 complex / TICAM1-dependent activation of IRF3/IRF7 / APC/C:Cdc20 mediated degradation of Cyclin B / Regulation of FZD by ubiquitination / Downregulation of ERBB4 signaling / p75NTR recruits signalling complexes / APC-Cdc20 mediated degradation of Nek2A / InlA-mediated entry of Listeria monocytogenes into host cells / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / Regulation of innate immune responses to cytosolic DNA / TRAF6-mediated induction of TAK1 complex within TLR4 complex / Regulation of pyruvate metabolism / NF-kB is activated and signals survival / Downregulation of ERBB2:ERBB3 signaling / Pexophagy / NRIF signals cell death from the nucleus / Regulation of PTEN localization / VLDLR internalisation and degradation / Activated NOTCH1 Transmits Signal to the Nucleus / neuron projection morphogenesis / Synthesis of active ubiquitin: roles of E1 and E2 enzymes / Regulation of BACH1 activity / MAP3K8 (TPL2)-dependent MAPK1/3 activation / regulation of mitochondrial membrane potential / TICAM1, RIP1-mediated IKK complex recruitment / Translesion synthesis by REV1 / Translesion synthesis by POLK / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / InlB-mediated entry of Listeria monocytogenes into host cell / Downregulation of TGF-beta receptor signaling / Josephin domain DUBs / ubiquitin binding / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / Translesion synthesis by POLI / Regulation of activated PAK-2p34 by proteasome mediated degradation / positive regulation of protein ubiquitination / IKK complex recruitment mediated by RIP1 / Gap-filling DNA repair synthesis and ligation in GG-NER / PINK1-PRKN Mediated Mitophagy / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / TNFR1-induced NF-kappa-B signaling pathway / Autodegradation of Cdh1 by Cdh1:APC/C / APC/C:Cdc20 mediated degradation of Securin / TCF dependent signaling in response to WNT / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / negative regulation of smoothened signaling pathway / Regulation of NF-kappa B signaling / Asymmetric localization of PCP proteins / Ubiquitin-dependent degradation of Cyclin D / SCF-beta-TrCP mediated degradation of Emi1 / NIK-->noncanonical NF-kB signaling / activated TAK1 mediates p38 MAPK activation / Negative regulators of DDX58/IFIH1 signaling / TNFR2 non-canonical NF-kB pathway / AUF1 (hnRNP D0) binds and destabilizes mRNA / Regulation of signaling by CBL
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 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 1 / : / Ubiquitin domain signature. / Ubiquitin conserved site / Ubiquitin domain / Ubiquitin-like (UB roll) / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Ubiquitin-like domain superfamily / Roll / Alpha Beta
Similarity search - Domain/homology
5-azanylpentan-2-one / E3 ubiquitin-protein ligase UBR5 / Polyubiquitin-B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsHehl, L.A. / Prabu, J.R. / Schulman, B.A.
Funding support Germany, 1items
OrganizationGrant numberCountry
Max Planck Society Germany
CitationJournal: Nat Chem Biol / Year: 2024
Title: Structural snapshots along K48-linked ubiquitin chain formation by the HECT E3 UBR5.
Authors: Laura A Hehl / Daniel Horn-Ghetko / J Rajan Prabu / Ronnald Vollrath / D Tung Vu / David A Pérez Berrocal / Monique P C Mulder / Gerbrand J van der Heden van Noort / Brenda A Schulman /
Abstract: Ubiquitin (Ub) chain formation by homologous to E6AP C-terminus (HECT)-family E3 ligases regulates vast biology, yet the structural mechanisms remain unknown. We used chemistry and cryo-electron ...Ubiquitin (Ub) chain formation by homologous to E6AP C-terminus (HECT)-family E3 ligases regulates vast biology, yet the structural mechanisms remain unknown. We used chemistry and cryo-electron microscopy (cryo-EM) to visualize stable mimics of the intermediates along K48-linked Ub chain formation by the human E3, UBR5. The structural data reveal a ≈ 620 kDa UBR5 dimer as the functional unit, comprising a scaffold with flexibly tethered Ub-associated (UBA) domains, and elaborately arranged HECT domains. Chains are forged by a UBA domain capturing an acceptor Ub, with its K48 lured into the active site by numerous interactions between the acceptor Ub, manifold UBR5 elements and the donor Ub. The cryo-EM reconstructions allow defining conserved HECT domain conformations catalyzing Ub transfer from E2 to E3 and from E3. Our data show how a full-length E3, ubiquitins to be adjoined, E2 and intermediary products guide a feed-forward HECT domain conformational cycle establishing a highly efficient, broadly targeting, K48-linked Ub chain forging machine.
History
DepositionDec 16, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 23, 2023Provider: repository / Type: Initial release
Revision 1.1Sep 6, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Feb 14, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year
Revision 1.3Oct 9, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: E3 ubiquitin-protein ligase UBR5
I: Polyubiquitin-B
K: Polyubiquitin-B
J: E3 ubiquitin-protein ligase UBR5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)637,7615
Polymers637,6604
Non-polymers1011
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
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: 310266.188 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: 503 K is mutated to R. 710 L is mutated to D. / Source: (gene. exp.) Homo sapiens (human) / Gene: UBR5, EDD, EDD1, HYD, KIAA0896 / Production host: Homo sapiens (human)
References: UniProt: O95071, HECT-type E3 ubiquitin transferase
#2: Protein Polyubiquitin-B


Mass: 8550.794 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: 48 LYS is mutated to CYS in the sequence / Source: (gene. exp.) Homo sapiens (human) / Gene: UBB / Production host: Escherichia coli (E. coli) / Strain (production host): BL21-Codon Plus (DE3)-RIL / References: UniProt: P0CG47
#3: Protein Polyubiquitin-B


Mass: 8576.831 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: UBB / Production host: Escherichia coli (E. coli) / Strain (production host): BL21-Codon Plus (DE3)-RIL / References: UniProt: P0CG47
#4: Chemical ChemComp-SY8 / 5-azanylpentan-2-one


Mass: 101.147 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H11NO
Has ligand of interestN
Has protein modificationY

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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: HECT E3 UBR5 forming K48 linked Ubiquitin chains / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightValue: 0.62 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Strain: HEK293S
Buffer solutionpH: 7.5
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 FIELD / Nominal defocus max: 2700 nm / Nominal defocus min: 700 nm
Image recordingElectron dose: 69 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 141034 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0045068
ELECTRON MICROSCOPYf_angle_d0.9166872
ELECTRON MICROSCOPYf_dihedral_angle_d5.658689
ELECTRON MICROSCOPYf_chiral_restr0.054788
ELECTRON MICROSCOPYf_plane_restr0.01902

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