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- EMDB-51429: Structure of HECT E3 TRIP12 forming K29/K48-branched Ubiquitin chains -

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Basic information

Entry
Database: EMDB / ID: EMD-51429
TitleStructure of HECT E3 TRIP12 forming K29/K48-branched Ubiquitin chains
Map datadeepEMhancer-sharpened map
Sample
  • Complex: TRIP12 deltaN K29/K48-branched chain formation complex
    • Protein or peptide: Ubiquitin
    • Protein or peptide: Polyubiquitin-C
    • Protein or peptide: Polyubiquitin-B
    • Protein or peptide: Isoform 3 of E3 ubiquitin-protein ligase TRIP12
  • Ligand: 5-azanylpentan-2-one
KeywordsLIGASE
Function / homology
Function and homology information


heterochromatin boundary formation / HECT-type E3 ubiquitin transferase / nuclear thyroid hormone receptor binding / symbiont entry into host cell via disruption of host cell glycocalyx / symbiont entry into host cell via disruption of host cell envelope / virus tail / DNA repair-dependent chromatin remodeling / regulation of embryonic development / Maturation of protein E / Maturation of protein E ...heterochromatin boundary formation / HECT-type E3 ubiquitin transferase / nuclear thyroid hormone receptor binding / symbiont entry into host cell via disruption of host cell glycocalyx / symbiont entry into host cell via disruption of host cell envelope / virus tail / DNA repair-dependent chromatin remodeling / regulation of embryonic development / 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 / 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 / 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 / Regulation of pyruvate metabolism / TRAF6-mediated induction of TAK1 complex within TLR4 complex / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / Regulation of innate immune responses to cytosolic DNA / NF-kB is activated and signals survival / Downregulation of ERBB2:ERBB3 signaling / NRIF signals cell death from the nucleus / Pexophagy / VLDLR internalisation and degradation / Regulation of PTEN localization / Activated NOTCH1 Transmits Signal to the Nucleus / Regulation of BACH1 activity / MAP3K8 (TPL2)-dependent MAPK1/3 activation / Translesion synthesis by REV1 / Synthesis of active ubiquitin: roles of E1 and E2 enzymes / 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 / Josephin domain DUBs / TICAM1, RIP1-mediated IKK complex recruitment / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / Translesion synthesis by POLI / Gap-filling DNA repair synthesis and ligation in GG-NER / IKK complex recruitment mediated by RIP1 / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / Regulation of activated PAK-2p34 by proteasome mediated degradation / TNFR1-induced NF-kappa-B signaling pathway / PINK1-PRKN Mediated Mitophagy / TCF dependent signaling in response to WNT / Autodegradation of Cdh1 by Cdh1:APC/C / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / APC/C:Cdc20 mediated degradation of Securin / activated TAK1 mediates p38 MAPK activation / Regulation of NF-kappa B signaling / Asymmetric localization of PCP proteins / Ubiquitin-dependent degradation of Cyclin D / Regulation of signaling by CBL / NIK-->noncanonical NF-kB signaling / NOTCH3 Activation and Transmission of Signal to the Nucleus / SCF-beta-TrCP mediated degradation of Emi1 / Negative regulators of DDX58/IFIH1 signaling / Deactivation of the beta-catenin transactivating complex / TNFR2 non-canonical NF-kB pathway / Negative regulation of FGFR3 signaling / AUF1 (hnRNP D0) binds and destabilizes mRNA / Fanconi Anemia Pathway / Vpu mediated degradation of CD4 / Assembly of the pre-replicative complex / Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A / Negative regulation of FGFR2 signaling / Degradation of DVL / Peroxisomal protein import / Negative regulation of FGFR4 signaling / Stabilization of p53 / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / Dectin-1 mediated noncanonical NF-kB signaling / Negative regulation of FGFR1 signaling / EGFR downregulation / Downregulation of SMAD2/3:SMAD4 transcriptional activity / Regulation of TNFR1 signaling / Termination of translesion DNA synthesis / Degradation of AXIN / Hh mutants are degraded by ERAD
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 / Pectate lyase superfamily protein ...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 / Pectate lyase superfamily protein / Rhamnogalacturonase A/epimerase, pectate lyase-like / Pectin lyase fold / Pectin lyase fold/virulence factor / : / Ubiquitin domain / Ubiquitin domain signature. / Ubiquitin conserved site / Armadillo-like helical / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Armadillo-type fold / Ubiquitin-like domain superfamily
Similarity search - Domain/homology
Tail fiber / Polyubiquitin-C / E3 ubiquitin-protein ligase TRIP12
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.69 Å
AuthorsMaiwald SA / Schulman BA
Funding support Germany, 2 items
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, 2024-
Header (metadata) releaseMay 21, 2025-
Map releaseMay 21, 2025-
UpdateJun 4, 2025-
Current statusJun 4, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_51429.png

Downloads & links

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Map

FileDownload / File: emd_51429.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationdeepEMhancer-sharpened map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 320 pix.
= 272.384 Å		0.85 Å/pix.
x 320 pix.
= 272.384 Å		0.85 Å/pix.
x 320 pix.
= 272.384 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8512 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.08
Minimum - Maximum-0.014902289 - 1.9432818
Average (Standard dev.)0.0012581414 (±0.023182532)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 272.384 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_51429_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Unsharpened map from non-uniform refinement

Fileemd_51429_additional_1.map
AnnotationUnsharpened map from non-uniform refinement
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 1 from non-uniform refinement

Fileemd_51429_half_map_1.map
AnnotationHalf map 1 from non-uniform refinement
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 2 from non-uniform refinement

Fileemd_51429_half_map_2.map
AnnotationHalf map 2 from non-uniform refinement
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : TRIP12 deltaN K29/K48-branched chain formation complex

EntireName: TRIP12 deltaN K29/K48-branched chain formation complex
Components
  • Complex: TRIP12 deltaN K29/K48-branched chain formation complex
    • Protein or peptide: Ubiquitin
    • Protein or peptide: Polyubiquitin-C
    • Protein or peptide: Polyubiquitin-B
    • Protein or peptide: Isoform 3 of E3 ubiquitin-protein ligase TRIP12
  • Ligand: 5-azanylpentan-2-one

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Supramolecule #1: TRIP12 deltaN K29/K48-branched chain formation complex

SupramoleculeName: TRIP12 deltaN K29/K48-branched chain formation complex
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 200 KDa

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Macromolecule #1: Ubiquitin

MacromoleculeName: Ubiquitin / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 8.519778 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MQIFVKTLTG KTITLEVEPS DTIENVKAKI QDKEGIPPDQ QRLIFAGKQL EDGRTLSDYN IQKESTLHLV LRLRG

UniProtKB: Polyubiquitin-C

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Macromolecule #2: Polyubiquitin-C

MacromoleculeName: Polyubiquitin-C / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 8.550794 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MQIFVKTLTG KTITLEVEPS DTIENVKACI QDKEGIPPDQ QRLIFAGKQL EDGRTLSDYN IQKESTLHLV LRLRGG

UniProtKB: Polyubiquitin-C

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Macromolecule #3: Polyubiquitin-B

MacromoleculeName: Polyubiquitin-B / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 8.604845 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MQIFVKTLTG KTITLEVEPS DTIENVKAKI QDKEGIPPDQ QRLIFAGRQL EDGRTLSDYN IQKESTLHLV LRLRGG

UniProtKB: Tail fiber

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Macromolecule #4: Isoform 3 of E3 ubiquitin-protein ligase TRIP12

MacromoleculeName: Isoform 3 of E3 ubiquitin-protein ligase TRIP12 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO / EC number: HECT-type E3 ubiquitin transferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 175.752453 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: GSTIGSGASS KAQQLLQGLQ ASDESQQLQA VIEMCQLLVM GNEETLGGFP VKSVVPALIT LLQMEHNFDI MNHACRALTY MMEALPRSS AVVVDAIPVF LEKLQVIQCI DVAEQALTAL EMLSRRHSKA ILQAGGLADC LLYLEFFSIN AQRNALAIAA N CCQSITPD ...String:
GSTIGSGASS KAQQLLQGLQ ASDESQQLQA VIEMCQLLVM GNEETLGGFP VKSVVPALIT LLQMEHNFDI MNHACRALTY MMEALPRSS AVVVDAIPVF LEKLQVIQCI DVAEQALTAL EMLSRRHSKA ILQAGGLADC LLYLEFFSIN AQRNALAIAA N CCQSITPD EFHFVADSLP LLTQRLTHQD KKSVESTCLC FARLVDNFQH EENLLQQVAS KDLLTNVQQL LVVTPPILSS GM FIMVVRM FSLMCSNCPT LAVQLMKQNI AETLHFLLCG ASNGSCQEQI DLVPRSPQEL YELTSLICEL MPCLPKEGIF AVD TMLKKG NAQNTDGAIW QWRDDRGLWH PYNRIDSRII EQINEDTGTA RAIQRKPNPL ANSNTSGYSE SKKDDARAQL MKED PELAK SFIKTLFGVL YEVYSSSAGP AVRHKCLRAI LRIIYFADAE LLKDVLKNHA VSSHIASMLS SQDLKIVVGA LQMAE ILMQ KLPDIFSVYF RREGVMHQVK HLAESESLLT SPPKACTNGS GSMGSTTSVS SGTATAATHA AADLGSPSLQ HSRDDS LDL SPQGRLSDVL KRKRLPKRGP RRPKYSPPRD DDKVDNQAKS PTTTQSPKSS FLASLNPKTW GRLSTQSNSN NIEPART AG GSGLARAASK DTISNNREKI KGWIKEQAHK FVERYFSSEN MDGSNPALNV LQRLCAATEQ LNLQVDGGAE CLVEIRSI V SESDVSSFEI QHSGFVKQLL LYLTSKSEKD AVSREIRLKR FLHVFFSSPL PGEEPIGRVE PVGNAPLLAL VHKMNNCLS QMEQFPVKVH DFPSGNGTGG SFSLNRGSQA LKFFNTHQLK CQLQRHPDCA NVKQWKGGPV KIDPLALVQA IERYLVVRGY GRVREDDED SDDDGSDEEI DESLAAQFLN SGNVRHRLQF YIGEHLLPYN MTVYQAVRQF SIQAEDERES TDDESNPLGR A GIWTKTHT IWYKPVREDE ESNKDCVGGK RGRAQTAPTK TSPRNAKKHD ELWHDGVCPS VSNPLEVYLI PTPPENITFE DP SLDVILL LRVLHAISRY WYYLYDNAMC KEIIPTSEFI NSKLTAKANR QLQDPLVIMT GNIPTWLTEL GKTCPFFFPF DTR QMLFYV TAFDRDRAMQ RLLDTNPEIN QSDSQDSRVA PRLDRKKRTV NREELLKQAE SVMQDLGSSR AMLEIQYENE VGTG LGPTL EFYALVSQEL QRADLGLWRG EEVTLSNPKG SQEGTKYIQN LQGLFALPFG RTAKPAHIAK VKMKFRFLGK LMAKA IMDF RLVDLPLGLP FYKWMLRQET SLTSHDLFDI DPVVARSVYH LEDIVRQKKR LEQDKSQTKE SLQYALETLT MNGCSV EDL GLDFTLPGFP NIELKKGGKD IPVTIHNLEE YLRLVIFWAL NEGVSRQFDS FRDGFESVFP LSHLQYFYPE ELDQLLC GS KADTWDAKTL MECCRPDHGY THDSRAVKFL FEILSSFDNE QQRLFLQFVT GSPRLPVGGF RSLNPPLTIV RKTFESTE N PDDFLPSVMT CVNYLKLPDY SSIEIMREKL LIAAREGQQS FHLS

UniProtKB: E3 ubiquitin-protein ligase TRIP12

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Macromolecule #5: 5-azanylpentan-2-one

MacromoleculeName: 5-azanylpentan-2-one / type: ligand / ID: 5 / Number of copies: 1 / Formula: SY8
Molecular weightTheoretical: 101.147 Da
Chemical component information

ChemComp-SY8:
5-azanylpentan-2-one

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 66.84 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.6 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER / Details: Ab-initio reconstruction in cryoSPARC
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.69 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 122281
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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