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- PDB-9qh5: Consensus structure of UBA6-UbDha-BIRC6 trapped ternary complex (... -

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Basic information

Entry
Database: PDB / ID: 9qh5
TitleConsensus structure of UBA6-UbDha-BIRC6 trapped ternary complex (doubly loaded)
Components
  • Dual E2 ubiquitin-conjugating enzyme/E3 ubiquitin-protein ligase BIRC6
  • Polyubiquitin-C
  • Ubiquitin-like modifier-activating enzyme 6
KeywordsLIGASE / Ubiquitin / E1 / E2 / SIGNALING PROTEIN
Function / homology
Function and homology information


FAT10 activating enzyme activity / E1 ubiquitin-activating enzyme / ubiquitin activating enzyme activity / labyrinthine layer development / (E3-independent) E2 ubiquitin-conjugating enzyme / ALK mutants bind TKIs / Flemming body / ubiquitin conjugating enzyme activity / microtubule organizing center / cysteine-type endopeptidase inhibitor activity ...FAT10 activating enzyme activity / E1 ubiquitin-activating enzyme / ubiquitin activating enzyme activity / labyrinthine layer development / (E3-independent) E2 ubiquitin-conjugating enzyme / ALK mutants bind TKIs / Flemming body / ubiquitin conjugating enzyme activity / microtubule organizing center / cysteine-type endopeptidase inhibitor activity / Maturation of protein E / Maturation of protein E / ER Quality Control Compartment (ERQC) / Myoclonic epilepsy of Lafora / FLT3 signaling by CBL mutants / IRAK2 mediated activation of TAK1 complex / Prevention of phagosomal-lysosomal fusion / 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 / Pexophagy / Downregulation of ERBB2:ERBB3 signaling / NRIF signals cell death from the nucleus / Regulation of PTEN localization / VLDLR internalisation and degradation / 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 / Translesion synthesis by POLK / InlB-mediated entry of Listeria monocytogenes into host cell / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / Josephin domain DUBs / Downregulation of TGF-beta receptor signaling / Translesion synthesis by POLI / Gap-filling DNA repair synthesis and ligation in GG-NER / Regulation of activated PAK-2p34 by proteasome mediated degradation / IKK complex recruitment mediated by RIP1 / regulation of cytokinesis / PINK1-PRKN Mediated Mitophagy / negative regulation of extrinsic apoptotic signaling pathway / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / TNFR1-induced NF-kappa-B signaling pathway / Autodegradation of Cdh1 by Cdh1:APC/C / TCF dependent signaling in response to WNT / APC/C:Cdc20 mediated degradation of Securin / Regulation of NF-kappa B signaling / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / Asymmetric localization of PCP proteins / activated TAK1 mediates p38 MAPK activation / Ubiquitin-dependent degradation of Cyclin D / 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 / Assembly of the pre-replicative complex / Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A / Negative regulation of FGFR3 signaling / Deactivation of the beta-catenin transactivating complex / Peroxisomal protein import / Fanconi Anemia Pathway / Degradation of DVL / Dectin-1 mediated noncanonical NF-kB signaling / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / Negative regulation of FGFR2 signaling / Stabilization of p53 / Negative regulation of FGFR4 signaling / trans-Golgi network / Downregulation of SMAD2/3:SMAD4 transcriptional activity / Negative regulation of FGFR1 signaling
Similarity search - Function
Baculoviral IAP repeat-containing protein 6 / Baculoviral IAP repeat-containing protein 6 / Ubiquitin-activating enzyme E1 / Ubiquitin-activating enzyme E1, C-terminal / Ubiquitin-activating enzyme E1, FCCH domain / Ubiquitin-activating enzyme E1, four-helix bundle / Ubiquitin-activating enzyme E1, C-terminal domain superfamily / Ubiquitin-activating enzyme E1, SCCH domain / Ubiquitin-activating enzyme E1, FCCH domain superfamily / Ubiquitin fold domain ...Baculoviral IAP repeat-containing protein 6 / Baculoviral IAP repeat-containing protein 6 / Ubiquitin-activating enzyme E1 / Ubiquitin-activating enzyme E1, C-terminal / Ubiquitin-activating enzyme E1, FCCH domain / Ubiquitin-activating enzyme E1, four-helix bundle / Ubiquitin-activating enzyme E1, C-terminal domain superfamily / Ubiquitin-activating enzyme E1, SCCH domain / Ubiquitin-activating enzyme E1, FCCH domain superfamily / Ubiquitin fold domain / Ubiquitin-activating enzyme E1 FCCH domain / Ubiquitin-activating enzyme E1 four-helix bundle / Ubiquitin-activating enzyme e1 C-terminal domain / Ubiquitin-activating enzyme, SCCH domain / Ubiquitin-activating enzyme, SCCH domain / Ubiquitin/SUMO-activating enzyme E1-like / Ubiquitin-activating enzyme E1, inactive adenylation domain, subdomain 1 / ThiF/MoeB/HesA family / THIF-type NAD/FAD binding fold / ThiF family / Ubiquitin-activating enzyme / BIR repeat / Inhibitor of Apoptosis domain / BIR repeat profile. / Baculoviral inhibition of apoptosis protein repeat / Ubiquitin-conjugating enzyme E2 / Ubiquitin-conjugating enzyme / Ubiquitin-conjugating (UBC) core domain profile. / Ubiquitin-conjugating enzyme E2, catalytic domain homologues / Ubiquitin-conjugating enzyme/RWD-like / : / Ubiquitin domain signature. / Ubiquitin conserved site / Ubiquitin domain / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Ubiquitin-like domain superfamily
Similarity search - Domain/homology
ADENOSINE MONOPHOSPHATE / INOSITOL HEXAKISPHOSPHATE / Ubiquitin-like modifier-activating enzyme 6 / Polyubiquitin-C / Dual E2 ubiquitin-conjugating enzyme/E3 ubiquitin-protein ligase BIRC6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.09 Å
AuthorsRiechmann, C. / Elliott, P.R.
Funding support United Kingdom, 2items
OrganizationGrant numberCountry
UK Research and Innovation (UKRI)BB/Y008936/1 United Kingdom
Cancer Research UKDRCPFA-Jun24/100003 United Kingdom
CitationJournal: Nat Struct Mol Biol / Year: 2025
Title: UBA6 specificity for ubiquitin E2 conjugating enzymes reveals a priority mechanism of BIRC6.
Authors: Carlos Riechmann / Cara J Ellison / Jake W Anderson / Kay Hofmann / Peter Sarkies / Paul R Elliott /
Abstract: In mammals, ubiquitylation is orchestrated by the canonical ubiquitin-activating E1 enzyme UBA1 and the orthogonal E1 UBA6. Growing evidence underscores the essentiality of both E1s, which ...In mammals, ubiquitylation is orchestrated by the canonical ubiquitin-activating E1 enzyme UBA1 and the orthogonal E1 UBA6. Growing evidence underscores the essentiality of both E1s, which differentiate between 29 active ubiquitin-conjugating enzymes (E2s). The mechanisms governing this distinction have remained unclear. Here we establish a framework for ubiquitin E1-E2 specificity. Focusing on UBA6-controlled ubiquitylation cascades, we reveal that BIRC6, a UBA6-exclusive E2, gains priority over all other UBA6-competent E2s, underpinning the functional importance of defined UBA6-BIRC6 ubiquitylation events in regulating cell death, embryogenesis and autophagy. By capturing BIRC6 receiving ubiquitin from UBA6 in different states, we observe BIRC6 engaging with the UBA6 ubiquitin fold domain, driving an exceptionally high-affinity interaction that is modulated by the UBA6 Cys-Cap loop. Using this interaction as a template, we demonstrate how to confer activity between E2s and their noncognate E1, providing a tool to delineate E1-E2-dependent pathways. Lastly, we explain how BIRC6 priority does not lead to inhibition of UBA6, through a bespoke thioester switch mechanism that disengages BIRC6 upon receiving ubiquitin. Our findings propose a concept of hierarchy of E2 activity with cognate E1s, which may explain how ubiquitin E1s can each function with over a dozen E2s and orchestrate E2-specific cellular functions.
History
DepositionMar 14, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 29, 2025Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Dual E2 ubiquitin-conjugating enzyme/E3 ubiquitin-protein ligase BIRC6
B: Ubiquitin-like modifier-activating enzyme 6
C: Polyubiquitin-C
E: Polyubiquitin-C
hetero molecules


Theoretical massNumber of molelcules
Total (without water)173,2746
Polymers172,2674
Non-polymers1,0072
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 Dual E2 ubiquitin-conjugating enzyme/E3 ubiquitin-protein ligase BIRC6 / BIR repeat-containing ubiquitin-conjugating enzyme / BRUCE / Baculoviral IAP repeat-containing ...BIR repeat-containing ubiquitin-conjugating enzyme / BRUCE / Baculoviral IAP repeat-containing protein 6 / Ubiquitin-conjugating BIR domain enzyme apollon / APOLLON


Mass: 36834.668 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BIRC6, KIAA1289 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Rosetta
References: UniProt: Q9NR09, (E3-independent) E2 ubiquitin-conjugating enzyme
#2: Protein Ubiquitin-like modifier-activating enzyme 6 / Ubiquitin-activating enzyme 6 / Monocyte protein 4 / MOP-4 / Ubiquitin-activating enzyme E1-like ...Ubiquitin-activating enzyme 6 / Monocyte protein 4 / MOP-4 / Ubiquitin-activating enzyme E1-like protein 2 / E1-L2


Mass: 118250.820 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: UBA6, MOP4, UBE1L2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: A0AVT1, E1 ubiquitin-activating enzyme
#3: Protein Polyubiquitin-C


Mass: 8590.856 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: UBC / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Rosetta / References: UniProt: P0CG48
#4: Chemical ChemComp-IHP / INOSITOL HEXAKISPHOSPHATE / MYO-INOSITOL HEXAKISPHOSPHATE / INOSITOL 1,2,3,4,5,6-HEXAKISPHOSPHATE


Mass: 660.035 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H18O24P6
#5: Chemical ChemComp-AMP / ADENOSINE MONOPHOSPHATE


Mass: 347.221 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H14N5O7P / Comment: AMP*YM
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: Trapped ternary complex of BIRC6 with UBA6 / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightValue: 0.17 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
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: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 37.84 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: 3.09 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 188172 / Symmetry type: POINT

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