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- PDB-8pjn: Catalytic module of human CTLH E3 ligase bound to multiphosphoryl... -

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Basic information

Entry
Database: PDB / ID: 8pjn
TitleCatalytic module of human CTLH E3 ligase bound to multiphosphorylated UBE2H~ubiquitin
Components
  • E3 ubiquitin-protein transferase MAEA
  • E3 ubiquitin-protein transferase RMND5A
  • Ubiquitin-conjugating enzyme E2 H
  • Ubiquitin
KeywordsLIGASE / E3 ubiquitin ligase / E2 ubiquitin-conjugating enzyme / phosphorylation / CTLH / GID / UBE2H
Function / homology
Function and homology information


GID complex / enucleate erythrocyte development / actomyosin contractile ring / (E3-independent) E2 ubiquitin-conjugating enzyme / negative regulation of myeloid cell apoptotic process / protein K11-linked ubiquitination / E2 ubiquitin-conjugating enzyme / ubiquitin conjugating enzyme activity / erythrocyte maturation / protein K48-linked ubiquitination ...GID complex / enucleate erythrocyte development / actomyosin contractile ring / (E3-independent) E2 ubiquitin-conjugating enzyme / negative regulation of myeloid cell apoptotic process / protein K11-linked ubiquitination / E2 ubiquitin-conjugating enzyme / ubiquitin conjugating enzyme activity / erythrocyte maturation / protein K48-linked ubiquitination / ubiquitin ligase complex / cytoskeleton organization / 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 / Constitutive Signaling by NOTCH1 HD Domain Mutants / Endosomal Sorting Complex Required For Transport (ESCRT) / NOTCH2 Activation and Transmission of Signal to the Nucleus / IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / Negative regulation of FLT3 / Regulation of FZD by ubiquitination / TICAM1,TRAF6-dependent induction of TAK1 complex / TICAM1-dependent activation of IRF3/IRF7 / APC/C:Cdc20 mediated degradation of Cyclin B / regulation of mitotic cell cycle / Downregulation of ERBB4 signaling / p75NTR recruits signalling complexes / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / APC-Cdc20 mediated degradation of Nek2A / PINK1-PRKN Mediated Mitophagy / TRAF6-mediated induction of TAK1 complex within TLR4 complex / InlA-mediated entry of Listeria monocytogenes into host cells / Pexophagy / Regulation of innate immune responses to cytosolic DNA / VLDLR internalisation and degradation / Downregulation of ERBB2:ERBB3 signaling / NRIF signals cell death from the nucleus / Activated NOTCH1 Transmits Signal to the Nucleus / Translesion synthesis by REV1 / NF-kB is activated and signals survival / Regulation of PTEN localization / Translesion synthesis by POLK / Regulation of BACH1 activity / Synthesis of active ubiquitin: roles of E1 and E2 enzymes / Translesion synthesis by POLI / Gap-filling DNA repair synthesis and ligation in GG-NER / MAP3K8 (TPL2)-dependent MAPK1/3 activation / TICAM1, RIP1-mediated IKK complex recruitment / Downregulation of TGF-beta receptor signaling / Josephin domain DUBs / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / Regulation of activated PAK-2p34 by proteasome mediated degradation / InlB-mediated entry of Listeria monocytogenes into host cell / IKK complex recruitment mediated by RIP1 / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / Autodegradation of Cdh1 by Cdh1:APC/C / TNFR1-induced NF-kappa-B signaling pathway / APC/C:Cdc20 mediated degradation of Securin / Asymmetric localization of PCP proteins / TCF dependent signaling in response to WNT / SCF-beta-TrCP mediated degradation of Emi1 / Regulation of NF-kappa B signaling / NIK-->noncanonical NF-kB signaling / Ubiquitin-dependent degradation of Cyclin D / AUF1 (hnRNP D0) binds and destabilizes mRNA / Negative regulators of DDX58/IFIH1 signaling / TNFR2 non-canonical NF-kB pathway / NOTCH3 Activation and Transmission of Signal to the Nucleus / activated TAK1 mediates p38 MAPK activation / Assembly of the pre-replicative complex / Vpu mediated degradation of CD4 / Deactivation of the beta-catenin transactivating complex / Degradation of DVL / Ubiquitin Mediated Degradation of Phosphorylated Cdc25A / Recognition of DNA damage by PCNA-containing replication complex / Regulation of signaling by CBL / Dectin-1 mediated noncanonical NF-kB signaling / Hh mutants are degraded by ERAD / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / Fanconi Anemia Pathway / Negative regulation of FGFR3 signaling / Termination of translesion DNA synthesis / Peroxisomal protein import / Degradation of AXIN / Downregulation of SMAD2/3:SMAD4 transcriptional activity / Regulation of TNFR1 signaling / Defective CFTR causes cystic fibrosis / Degradation of GLI1 by the proteasome
Similarity search - Function
Protein RMD5 homologue A, degenerated RING finger / Fyv10 family / Gid-type RING finger domain / Gid-type RING finger profile. / CRA domain / CT11-RanBPM / CTLH/CRA C-terminal to LisH motif domain / CTLH/CRA C-terminal to LisH motif domain / C-terminal to LisH motif. / CTLH, C-terminal LisH motif ...Protein RMD5 homologue A, degenerated RING finger / Fyv10 family / Gid-type RING finger domain / Gid-type RING finger profile. / CRA domain / CT11-RanBPM / CTLH/CRA C-terminal to LisH motif domain / CTLH/CRA C-terminal to LisH motif domain / C-terminal to LisH motif. / CTLH, C-terminal LisH motif / C-terminal to LisH (CTLH) motif profile. / Zinc finger, RING-type, eukaryotic / RING-type zinc-finger / Lissencephaly type-1-like homology motif / LIS1 homology (LisH) motif profile. / LIS1 homology motif / Ubiquitin-conjugating enzyme, active site / Ubiquitin-conjugating (UBC) active site signature. / Ubiquitin-conjugating enzyme E2, catalytic domain homologues / Ubiquitin-conjugating enzyme E2 / Ubiquitin-conjugating enzyme / Ubiquitin-conjugating (UBC) core domain profile. / Ubiquitin-conjugating enzyme/RWD-like / Ubiquitin conserved site / Ubiquitin domain / Ubiquitin domain signature. / Ubiquitin family / Ubiquitin homologues / Ubiquitin-like domain / Ubiquitin domain profile. / Ubiquitin-like domain superfamily
Similarity search - Domain/homology
Polyubiquitin-C / Ubiquitin-conjugating enzyme E2 H / E3 ubiquitin-protein transferase MAEA / E3 ubiquitin-protein transferase RMND5A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsChrustowicz, J. / Sherpa, D. / Prabu, R.J. / Schulman, B.A.
Funding support Germany, European Union, 3items
OrganizationGrant numberCountry
Max Planck Society Germany
European Research Council (ERC)H2020 789016-NEDD8ActivateEuropean Union
German Research Foundation (DFG)SCHU 3196/1-1 Germany
CitationJournal: Mol Cell / Year: 2024
Title: Multisite phosphorylation dictates selective E2-E3 pairing as revealed by Ubc8/UBE2H-GID/CTLH assemblies.
Authors: Jakub Chrustowicz / Dawafuti Sherpa / Jerry Li / Christine R Langlois / Eleftheria C Papadopoulou / D Tung Vu / Laura A Hehl / Özge Karayel / Viola Beier / Susanne von Gronau / Judith ...Authors: Jakub Chrustowicz / Dawafuti Sherpa / Jerry Li / Christine R Langlois / Eleftheria C Papadopoulou / D Tung Vu / Laura A Hehl / Özge Karayel / Viola Beier / Susanne von Gronau / Judith Müller / J Rajan Prabu / Matthias Mann / Gary Kleiger / Arno F Alpi / Brenda A Schulman /
Abstract: Ubiquitylation is catalyzed by coordinated actions of E3 and E2 enzymes. Molecular principles governing many important E3-E2 partnerships remain unknown, including those for RING-family GID/CTLH E3 ...Ubiquitylation is catalyzed by coordinated actions of E3 and E2 enzymes. Molecular principles governing many important E3-E2 partnerships remain unknown, including those for RING-family GID/CTLH E3 ubiquitin ligases and their dedicated E2, Ubc8/UBE2H (yeast/human nomenclature). GID/CTLH-Ubc8/UBE2H-mediated ubiquitylation regulates biological processes ranging from yeast metabolic signaling to human development. Here, cryoelectron microscopy (cryo-EM), biochemistry, and cell biology reveal this exquisitely specific E3-E2 pairing through an unconventional catalytic assembly and auxiliary interactions 70-100 Å away, mediated by E2 multisite phosphorylation. Rather than dynamic polyelectrostatic interactions reported for other ubiquitylation complexes, multiple Ubc8/UBE2H phosphorylation sites within acidic CK2-targeted sequences specifically anchor the E2 C termini to E3 basic patches. Positions of phospho-dependent interactions relative to the catalytic domains correlate across evolution. Overall, our data show that phosphorylation-dependent multivalency establishes a specific E3-E2 partnership, is antagonistic with dephosphorylation, rigidifies the catalytic centers within a flexing GID E3-substrate assembly, and facilitates substrate collision with ubiquitylation active sites.
History
DepositionJun 23, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 3, 2024Provider: repository / Type: Initial release
Revision 1.1Jan 24, 2024Group: Derived calculations
Category: pdbx_struct_sheet_hbond / struct_conf ...pdbx_struct_sheet_hbond / struct_conf / struct_sheet / struct_sheet_order / struct_sheet_range
Item: _pdbx_struct_sheet_hbond.range_1_auth_asym_id / _pdbx_struct_sheet_hbond.range_1_auth_atom_id ..._pdbx_struct_sheet_hbond.range_1_auth_asym_id / _pdbx_struct_sheet_hbond.range_1_auth_atom_id / _pdbx_struct_sheet_hbond.range_1_auth_comp_id / _pdbx_struct_sheet_hbond.range_1_auth_seq_id / _pdbx_struct_sheet_hbond.range_1_label_asym_id / _pdbx_struct_sheet_hbond.range_1_label_atom_id / _pdbx_struct_sheet_hbond.range_1_label_comp_id / _pdbx_struct_sheet_hbond.range_1_label_seq_id / _pdbx_struct_sheet_hbond.range_2_auth_asym_id / _pdbx_struct_sheet_hbond.range_2_auth_atom_id / _pdbx_struct_sheet_hbond.range_2_auth_comp_id / _pdbx_struct_sheet_hbond.range_2_auth_seq_id / _pdbx_struct_sheet_hbond.range_2_label_asym_id / _pdbx_struct_sheet_hbond.range_2_label_atom_id / _pdbx_struct_sheet_hbond.range_2_label_comp_id / _pdbx_struct_sheet_hbond.range_2_label_seq_id / _pdbx_struct_sheet_hbond.range_id_1 / _pdbx_struct_sheet_hbond.range_id_2 / _pdbx_struct_sheet_hbond.sheet_id / _struct_sheet_order.range_id_1 / _struct_sheet_order.range_id_2 / _struct_sheet_order.sense / _struct_sheet_order.sheet_id
Revision 1.2Jan 31, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
b: E3 ubiquitin-protein transferase RMND5A
2: Ubiquitin-conjugating enzyme E2 H
i: E3 ubiquitin-protein transferase MAEA
u: Ubiquitin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)119,3686
Polymers119,2384
Non-polymers1312
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 E3 ubiquitin-protein transferase RMND5A / P44CTLH / Protein RMD5 homolog A


Mass: 44043.449 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RMND5A / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: Q9H871, RING-type E3 ubiquitin transferase
#2: Protein Ubiquitin-conjugating enzyme E2 H / (E3-independent) E2 ubiquitin-conjugating enzyme H / E2 ubiquitin-conjugating enzyme H / UbcH2 / ...(E3-independent) E2 ubiquitin-conjugating enzyme H / E2 ubiquitin-conjugating enzyme H / UbcH2 / Ubiquitin carrier protein H / Ubiquitin-conjugating enzyme E2-20K / Ubiquitin-protein ligase H


Mass: 21260.986 Da / Num. of mol.: 1 / Mutation: C87K
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: UBE2H / Production host: Trichoplusia (butterflies/moths)
References: UniProt: P62256, E2 ubiquitin-conjugating enzyme, (E3-independent) E2 ubiquitin-conjugating enzyme
#3: Protein E3 ubiquitin-protein transferase MAEA / Cell proliferation-inducing gene 5 protein / Erythroblast macrophage protein / Human lung cancer ...Cell proliferation-inducing gene 5 protein / Erythroblast macrophage protein / Human lung cancer oncogene 10 protein / HLC-10 / Macrophage erythroblast attacher / P44EMLP


Mass: 45356.332 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAEA, EMP, HLC10, PIG5 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: Q7L5Y9, RING-type E3 ubiquitin transferase
#4: Protein Ubiquitin / / Polyubiquitin-C


Mass: 8576.831 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: UBC / Production host: Escherichia coli (E. coli) / References: UniProt: P0CG48
#5: 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 CTLHSR4 E3 ligase bound to engineered ARMC8-specific VH and multiphosphorylated UBE2H~ubiquitin
Type: COMPLEX
Details: Map obtained by focus refinement over the catalytic module (RMND5A, MAEA) and UBE2H~ubiquitin
Entity ID: #1-#4 / Source: RECOMBINANT
Molecular weightValue: 0.6 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
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: 68 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 45472 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0037047
ELECTRON MICROSCOPYf_angle_d0.4959570
ELECTRON MICROSCOPYf_dihedral_angle_d4.6141010
ELECTRON MICROSCOPYf_chiral_restr0.0391114
ELECTRON MICROSCOPYf_plane_restr0.0031216

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