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- PDB-9gkm: Structure of HECT E3 TRIP12 forming K29/K48-branched Ubiquitin chains -

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Basic information

Entry
Database: PDB / ID: 9gkm
TitleStructure of HECT E3 TRIP12 forming K29/K48-branched Ubiquitin chains
Components
  • Isoform 3 of E3 ubiquitin-protein ligase TRIP12
  • Polyubiquitin-B
  • Polyubiquitin-C
  • Ubiquitin
KeywordsLIGASE
Function / homology
Function and homology information


heterochromatin boundary formation / HECT-type E3 ubiquitin transferase / hypothalamus gonadotrophin-releasing hormone neuron development / nuclear thyroid hormone receptor binding / female meiosis I / positive regulation of protein monoubiquitination / fat pad development / mitochondrion transport along microtubule / female gonad development / DNA repair-dependent chromatin remodeling ...heterochromatin boundary formation / HECT-type E3 ubiquitin transferase / hypothalamus gonadotrophin-releasing hormone neuron development / nuclear thyroid hormone receptor binding / female meiosis I / positive regulation of protein monoubiquitination / fat pad development / mitochondrion transport along microtubule / female gonad development / DNA repair-dependent chromatin remodeling / seminiferous tubule development / male meiosis I / positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator / regulation of embryonic development / energy homeostasis / regulation of neuron apoptotic process / neuron projection morphogenesis / 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 / Endosomal Sorting Complex Required For Transport (ESCRT) / Membrane binding and targetting of GAG proteins / Negative regulation of FLT3 / Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7 / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / Regulation of TBK1, IKKε-mediated activation of IRF3, IRF7 upon TLR3 ligation / Constitutive Signaling by NOTCH1 HD Domain Mutants / 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 / Downregulation of ERBB4 signaling / Regulation of FZD by ubiquitination / APC-Cdc20 mediated degradation of Nek2A / p75NTR recruits signalling complexes / InlA-mediated entry of Listeria monocytogenes into host cells / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / TRAF6-mediated induction of TAK1 complex within TLR4 complex / Regulation of pyruvate metabolism / NF-kB is activated and signals survival / Regulation of innate immune responses to cytosolic DNA / Downregulation of ERBB2:ERBB3 signaling / Pexophagy / NRIF signals cell death from the nucleus / VLDLR internalisation and degradation / Regulation of PTEN localization / Activated NOTCH1 Transmits Signal to the Nucleus / Regulation of BACH1 activity / Synthesis of active ubiquitin: roles of E1 and E2 enzymes / MAP3K8 (TPL2)-dependent MAPK1/3 activation / Translesion synthesis by REV1 / TICAM1, RIP1-mediated IKK complex recruitment / InlB-mediated entry of Listeria monocytogenes into host cell / Translesion synthesis by POLK / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / Downregulation of TGF-beta receptor signaling / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / Josephin domain DUBs / Translesion synthesis by POLI / Regulation of activated PAK-2p34 by proteasome mediated degradation / Gap-filling DNA repair synthesis and ligation in GG-NER / IKK complex recruitment mediated by RIP1 / positive regulation of protein ubiquitination / 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 / regulation of mitochondrial membrane potential / APC/C:Cdc20 mediated degradation of Securin / TCF dependent signaling in response to WNT / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / Regulation of NF-kappa B signaling / Asymmetric localization of PCP proteins / Ubiquitin-dependent degradation of Cyclin D / activated TAK1 mediates p38 MAPK activation / SCF-beta-TrCP mediated degradation of Emi1 / NIK-->noncanonical NF-kB signaling / TNFR2 non-canonical NF-kB pathway / AUF1 (hnRNP D0) binds and destabilizes mRNA / Regulation of signaling by CBL / Vpu mediated degradation of CD4 / NOTCH3 Activation and Transmission of Signal to the Nucleus / Negative regulators of DDX58/IFIH1 signaling / Deactivation of the beta-catenin transactivating complex / Assembly of the pre-replicative complex / Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A / Degradation of DVL / Negative regulation of FGFR3 signaling / Fanconi Anemia Pathway / Peroxisomal protein import
Similarity search - Function
E3 ubiquitin-protein ligase HECTD1/TRIP12-like / WWE domain superfamily / WWE domain / WWE domain profile. / HECT domain / HECT, E3 ligase catalytic domain / HECT-domain (ubiquitin-transferase) / HECT domain profile. / Domain Homologous to E6-AP Carboxyl Terminus with / : ...E3 ubiquitin-protein ligase HECTD1/TRIP12-like / WWE domain superfamily / WWE domain / WWE domain profile. / HECT domain / HECT, E3 ligase catalytic domain / HECT-domain (ubiquitin-transferase) / HECT domain profile. / Domain Homologous to E6-AP Carboxyl Terminus with / : / Ubiquitin domain signature. / Ubiquitin conserved site / Ubiquitin domain / Armadillo-like helical / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Armadillo-type fold / Ubiquitin-like domain superfamily
Similarity search - Domain/homology
5-azanylpentan-2-one / Polyubiquitin-B / Polyubiquitin-C / E3 ubiquitin-protein ligase TRIP12
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.69 Å
AuthorsMaiwald, S.A. / Schulman, B.A.
Funding support Germany, 2items
OrganizationGrant numberCountry
German Research Foundation (DFG)SFB1035 Germany
Boehringer Ingelheim Fonds (BIF) Germany
CitationJournal: Nat Struct Mol Biol / Year: 2025
Title: TRIP12 structures reveal HECT E3 formation of K29 linkages and branched ubiquitin chains.
Authors: Samuel A Maiwald / Laura A Schneider / Ronnald Vollrath / Joanna Liwocha / Matthew D Maletic / Kirby N Swatek / Monique P C Mulder / Brenda A Schulman /
Abstract: Regulation by ubiquitin depends on E3 ligases forging chains of specific topologies, yet the mechanisms underlying the generation of atypical linkages remain largely elusive. Here we utilize ...Regulation by ubiquitin depends on E3 ligases forging chains of specific topologies, yet the mechanisms underlying the generation of atypical linkages remain largely elusive. Here we utilize biochemistry, chemistry, and cryo-EM to define the catalytic architecture producing K29 linkages and K29/K48 branches for the human HECT E3 TRIP12. TRIP12 resembles a pincer. One pincer side comprises tandem ubiquitin-binding domains, engaging the proximal ubiquitin to direct its K29 towards the ubiquitylation active site, and selectively capturing a distal ubiquitin from a K48-linked chain. The opposite pincer side-the HECT domain-precisely juxtaposes the ubiquitins to be joined, further ensuring K29 linkage specificity. Comparison to the prior structure visualizing K48-linked chain formation by UBR5 reveals a similar mechanism shared by two human HECT enzymes: parallel features of the E3s, donor and acceptor ubiquitins configure the active site around the targeted lysine, with E3-specific domains buttressing the acceptor for linkage-specific polyubiquitylation.
History
DepositionAug 25, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 21, 2025Provider: repository / Type: Initial release
Revision 1.1Jun 4, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _em_admin.last_update
Revision 1.2Oct 1, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Ubiquitin
C: Polyubiquitin-C
D: Polyubiquitin-B
A: Isoform 3 of E3 ubiquitin-protein ligase TRIP12
hetero molecules


Theoretical massNumber of molelcules
Total (without water)201,5295
Polymers201,4284
Non-polymers1011
Water00
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 Ubiquitin


Mass: 8519.778 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
#2: Protein Polyubiquitin-C


Mass: 8550.794 Da / Num. of mol.: 1 / Mutation: K29C
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
#3: Protein Polyubiquitin-B


Mass: 8604.845 Da / Num. of mol.: 1 / Mutation: K48R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: UBB / Production host: Escherichia coli (E. coli) / References: UniProt: P0CG47
#4: Protein Isoform 3 of E3 ubiquitin-protein ligase TRIP12 / E3 ubiquitin-protein ligase for Arf / ULF / HECT-type E3 ubiquitin transferase TRIP12 / Thyroid ...E3 ubiquitin-protein ligase for Arf / ULF / HECT-type E3 ubiquitin transferase TRIP12 / Thyroid receptor-interacting protein 12 / TR-interacting protein 12 / TRIP-12


Mass: 175752.453 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TRIP12, KIAA0045, ULF / Production host: Escherichia coli (E. coli)
References: UniProt: Q14669, HECT-type E3 ubiquitin transferase
#5: 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: TRIP12 deltaN K29/K48-branched chain formation complex
Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Molecular weightValue: 0.2 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-PROPANE

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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: 2200 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 66.84 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.21.1_5286 / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.69 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 122281 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00211442
ELECTRON MICROSCOPYf_angle_d0.4715513
ELECTRON MICROSCOPYf_dihedral_angle_d3.5371536
ELECTRON MICROSCOPYf_chiral_restr0.0381818
ELECTRON MICROSCOPYf_plane_restr0.0041984

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