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- PDB-9plq: HUWE1(CS)-Ubiquitin bound to the HECT domain -

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Basic information

Entry
Database: PDB / ID: 9plq
TitleHUWE1(CS)-Ubiquitin bound to the HECT domain
Components
  • E3 ubiquitin-protein ligase HUWE1
  • Ubiquitin
KeywordsLIGASE / Ubiquitin complex / HUWE1 / E3 ligase
Function / homology
Function and homology information


negative regulation of peroxisome proliferator activated receptor signaling pathway / histone ubiquitin ligase activity / negative regulation of mitochondrial fusion / protein branched polyubiquitination / positive regulation of type 2 mitophagy / HECT-type E3 ubiquitin transferase / positive regulation of protein localization to mitochondrion / ubiquitin-ubiquitin ligase activity / Golgi organization / protein monoubiquitination ...negative regulation of peroxisome proliferator activated receptor signaling pathway / histone ubiquitin ligase activity / negative regulation of mitochondrial fusion / protein branched polyubiquitination / positive regulation of type 2 mitophagy / HECT-type E3 ubiquitin transferase / positive regulation of protein localization to mitochondrion / ubiquitin-ubiquitin ligase activity / Golgi organization / protein monoubiquitination / protein K48-linked ubiquitination / 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 / Alpha-protein kinase 1 signaling pathway / Glycogen synthesis / IRAK1 recruits IKK complex / IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation / Prevention of phagosomal-lysosomal fusion / Endosomal Sorting Complex Required For Transport (ESCRT) / Membrane binding and targetting of GAG proteins / Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7 / Negative regulation of FLT3 / Regulation of TBK1, IKKε-mediated activation of IRF3, IRF7 upon TLR3 ligation / IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation / Constitutive Signaling by NOTCH1 HD Domain Mutants / NOTCH2 Activation and Transmission of Signal to the Nucleus / TICAM1,TRAF6-dependent induction of TAK1 complex / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / TICAM1-dependent activation of IRF3/IRF7 / APC/C:Cdc20 mediated degradation of Cyclin B / Downregulation of ERBB4 signaling / positive regulation of protein ubiquitination / APC-Cdc20 mediated degradation of Nek2A / Regulation of FZD by ubiquitination / p75NTR recruits signalling complexes / InlA-mediated entry of Listeria monocytogenes into host cells / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / NF-kB is activated and signals survival / TRAF6-mediated induction of TAK1 complex within TLR4 complex / Regulation of pyruvate metabolism / Pexophagy / PD-L1(CD274) glycosylation and translocation to plasma membrane / NRIF signals cell death from the nucleus / Downregulation of ERBB2:ERBB3 signaling / Regulation of PTEN localization / Regulation of innate immune responses to cytosolic DNA / VLDLR internalisation and degradation / Activated NOTCH1 Transmits Signal to the Nucleus / Translesion synthesis by REV1 / TICAM1, RIP1-mediated IKK complex recruitment / Synthesis of active ubiquitin: roles of E1 and E2 enzymes / ZNF598 and the Ribosome-associated Quality Trigger (RQT) complex dissociate a ribosome stalled on a no-go mRNA / Translesion synthesis by POLK / Regulation of BACH1 activity / InlB-mediated entry of Listeria monocytogenes into host cell / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / MAP3K8 (TPL2)-dependent MAPK1/3 activation / Translesion synthesis by POLI / Downregulation of TGF-beta receptor signaling / Josephin domain DUBs / Gap-filling DNA repair synthesis and ligation in GG-NER / IKK complex recruitment mediated by RIP1 / PINK1-PRKN Mediated Mitophagy / circadian regulation of gene expression / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / TNFR1-induced NF-kappa-B signaling pathway / Regulation of activated PAK-2p34 by proteasome mediated degradation / TCF dependent signaling in response to WNT / activated TAK1 mediates p38 MAPK activation / Regulation of NF-kappa B signaling / Maturation of DENV proteins / Autodegradation of Cdh1 by Cdh1:APC/C / APC/C:Cdc20 mediated degradation of Securin / NOTCH3 Activation and Transmission of Signal to the Nucleus / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / Regulation of signaling by CBL / Negative regulators of DDX58/IFIH1 signaling / Asymmetric localization of PCP proteins / Negative regulation of FGFR3 signaling / Ubiquitin-dependent degradation of Cyclin D / Peroxisomal protein import / Fanconi Anemia Pathway / SCF-beta-TrCP mediated degradation of Emi1 / AUF1 (hnRNP D0) binds and destabilizes mRNA / NIK-->noncanonical NF-kB signaling / Stabilization of p53 / TNFR2 non-canonical NF-kB pathway / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling / Enterobacterial factors antagonize host defense / Negative regulation of FGFR1 signaling / Termination of translesion DNA synthesis / Downregulation of SMAD2/3:SMAD4 transcriptional activity / Assembly of the pre-replicative complex / EGFR downregulation
Similarity search - Function
HUWE1, UBA domain / E3 ubiquitin ligase, domain of unknown function DUF908 / E3 ubiquitin ligase, domain of unknown function DUF913 / Domain of Unknown Function (DUF908) / Domain of Unknown Function (DUF913) / WWE domain / UBA-like domain / WWE domain superfamily / WWE domain / WWE domain profile. ...HUWE1, UBA domain / E3 ubiquitin ligase, domain of unknown function DUF908 / E3 ubiquitin ligase, domain of unknown function DUF913 / Domain of Unknown Function (DUF908) / Domain of Unknown Function (DUF913) / WWE domain / UBA-like domain / WWE domain superfamily / WWE domain / WWE domain profile. / HUWE1/Rev1, ubiquitin binding region / Ubiquitin binding region / Ubiquitin-binding motif (UBM) 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 associated domain / Ubiquitin-associated domain / Ubiquitin-associated domain (UBA) profile. / UBA-like superfamily / : / Ubiquitin domain signature. / Ubiquitin conserved site / Ubiquitin domain / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Armadillo-type fold / Ubiquitin-like domain superfamily
Similarity search - Domain/homology
Polyubiquitin-C / E3 ubiquitin-protein ligase HUWE1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.19 Å
AuthorsYatskevich, S. / Juszkiewicz, S.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Mol Cell / Year: 2026
Title: Molecular mechanism of HUWE1-HAPSTR1-USP7-mediated ubiquitin chain amplification on nuclear proteins.
Authors: Stanislau Yatskevich / Jugal Mohapatra / Rana Mroue / Lilian Phu / Alexander Leitner / Caleigh M Azumaya / Richard Vandlen / Tommy K Cheung / Tik Hang Soong / Christopher M Rose / Alessandro ...Authors: Stanislau Yatskevich / Jugal Mohapatra / Rana Mroue / Lilian Phu / Alexander Leitner / Caleigh M Azumaya / Richard Vandlen / Tommy K Cheung / Tik Hang Soong / Christopher M Rose / Alessandro Ori / Claudio Ciferri / Szymon Juszkiewicz /
Abstract: Rapid protein turnover is essential for cellular stress adaptation. HUWE1 (HECT, UBA, and WWE domain containing 1), a large HECT-type E3 ligase, regulates many short-lived stress-responsive proteins, ...Rapid protein turnover is essential for cellular stress adaptation. HUWE1 (HECT, UBA, and WWE domain containing 1), a large HECT-type E3 ligase, regulates many short-lived stress-responsive proteins, yet the mechanisms underlying its substrate selectivity remain unclear. Here, we reveal that HUWE1 functions as a ubiquitin chain amplifier that captures pre-ubiquitinated substrates and amplifies the degradation signal by assembling long ubiquitin chains containing K11-K48 branch points, a process regulated by its partners HUWE1-associated protein stress response 1 (HAPSTR1) and USP7 (ubiquitin-specific-processing protease 7). Structural and biochemical analyses show that HAPSTR1 engages HUWE1's ubiquitin-binding motifs to drive nuclear import and modulate substrate recruitment. A cryo-EM structure of the HUWE1-USP7 complex reveals a bidirectional regulatory mechanism: HUWE1 activates USP7's catalytic activity, while USP7 modulates HUWE1 conformational states. Global proteomic analyses demonstrate that this axis drives extensive remodeling of the short-lived nuclear proteome. These findings establish the HUWE1-HAPSTR1-USP7 complex as a key ubiquitin code modifier, providing a molecular rationale for HUWE1 dysregulation in neurodevelopmental disorders and cancer.
History
DepositionJul 16, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 22, 2026Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: E3 ubiquitin-protein ligase HUWE1
B: Ubiquitin


Theoretical massNumber of molelcules
Total (without water)490,9852
Polymers490,9852
Non-polymers00
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 E3 ubiquitin-protein ligase HUWE1 / ARF-binding protein 1 / ARF-BP1 / HECT / UBA and WWE domain-containing protein 1 / HECT-type E3 ...ARF-binding protein 1 / ARF-BP1 / HECT / UBA and WWE domain-containing protein 1 / HECT-type E3 ubiquitin transferase HUWE1 / Homologous to E6AP carboxyl terminus homologous protein 9 / HectH9 / Large structure of UREB1 / LASU1 / Mcl-1 ubiquitin ligase E3 / Mule / Upstream regulatory element-binding protein 1 / URE-B1 / URE-binding protein 1


Mass: 482408.281 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HUWE1, KIAA0312, KIAA1578, UREB1, HSPC272 / Production host: Homo sapiens (human)
References: UniProt: Q7Z6Z7, HECT-type E3 ubiquitin transferase
#2: Protein Ubiquitin


Mass: 8576.831 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P0CG48
Has protein modificationN

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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: HUWE1-Ubiquitin complex / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
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: 1600 nm / Nominal defocus min: 900 nm
Image recordingElectron dose: 45 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX2.0_5936model refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.19 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 105530 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 168.47 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.003819838
ELECTRON MICROSCOPYf_angle_d0.907726841
ELECTRON MICROSCOPYf_chiral_restr0.04953172
ELECTRON MICROSCOPYf_plane_restr0.01033379
ELECTRON MICROSCOPYf_dihedral_angle_d6.1922632

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