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- PDB-9plr: CryoEM reconstruction of HUWE1-USP7 complex in the closed state -

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Basic information

Entry
Database: PDB / ID: 9plr
TitleCryoEM reconstruction of HUWE1-USP7 complex in the closed state
Components
  • E3 ubiquitin-protein ligase HUWE1
  • Ubiquitin carboxyl-terminal hydrolase 7
KeywordsLIGASE / Complex / E3-ligase-DUB
Function / homology
Function and homology information


negative regulation of peroxisome proliferator activated receptor signaling pathway / regulation of telomere capping / histone H2B deubiquitinase activity / histone ubiquitin ligase activity / histone H2A deubiquitinase activity / negative regulation of mitochondrial fusion / regulation of establishment of protein localization to telomere / monoubiquitinated protein deubiquitination / protein branched polyubiquitination / peptidase complex ...negative regulation of peroxisome proliferator activated receptor signaling pathway / regulation of telomere capping / histone H2B deubiquitinase activity / histone ubiquitin ligase activity / histone H2A deubiquitinase activity / negative regulation of mitochondrial fusion / regulation of establishment of protein localization to telomere / monoubiquitinated protein deubiquitination / protein branched polyubiquitination / peptidase complex / regulation of retrograde transport, endosome to Golgi / positive regulation of type 2 mitophagy / DNA alkylation repair / deubiquitinase activity / HECT-type E3 ubiquitin transferase / protein K48-linked deubiquitination / K48-linked deubiquitinase activity / regulation of tumor necrosis factor-mediated signaling pathway / symbiont-mediated disruption of host cell PML body / positive regulation of protein localization to mitochondrion / ubiquitin-ubiquitin ligase activity / negative regulation of gene expression via chromosomal CpG island methylation / protein K63-linked deubiquitination / Golgi organization / negative regulation of gluconeogenesis / protein monoubiquitination / protein deubiquitination / ubiquitin ligase complex / protein K48-linked ubiquitination / negative regulation of proteasomal ubiquitin-dependent protein catabolic process / transcription-coupled nucleotide-excision repair / negative regulation of TORC1 signaling / positive regulation of protein ubiquitination / regulation of signal transduction by p53 class mediator / Regulation of PTEN localization / Synthesis of active ubiquitin: roles of E1 and E2 enzymes / circadian regulation of gene expression / regulation of protein stability / antiviral innate immune response / PML body / base-excision repair / regulation of circadian rhythm / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / protein polyubiquitination / p53 binding / ubiquitin-protein transferase activity / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / Regulation of TP53 Degradation / ubiquitin protein ligase activity / Antigen processing: Ubiquitination & Proteasome degradation / nuclear membrane / secretory granule lumen / ubiquitin-dependent protein catabolic process / ficolin-1-rich granule lumen / proteasome-mediated ubiquitin-dependent protein catabolic process / membrane fusion / nuclear body / positive regulation of canonical NF-kappaB signal transduction / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / protein stabilization / protein ubiquitination / Ub-specific processing proteases / chromosome / Golgi membrane / cysteine-type endopeptidase activity / Neutrophil degranulation / protein-containing complex / mitochondrion / DNA binding / RNA binding / extracellular exosome / nucleoplasm / extracellular region / membrane / nucleus / cytosol / cytoplasm
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 / Ubiquitin carboxyl-terminal hydrolase 7, ICP0-binding domain / ICP0-binding domain of Ubiquitin-specific protease 7 / Ubiquitin carboxyl-terminal hydrolase, C-terminal ...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 / Ubiquitin carboxyl-terminal hydrolase 7, ICP0-binding domain / ICP0-binding domain of Ubiquitin-specific protease 7 / Ubiquitin carboxyl-terminal hydrolase, C-terminal / Ubiquitin-specific protease C-terminal / WWE domain superfamily / WWE domain / WWE domain profile. / HUWE1/Rev1, ubiquitin binding region / Ubiquitin binding region / MATH domain / Ubiquitin-binding motif (UBM) domain profile. / : / : / MATH/TRAF domain / MATH/TRAF domain profile. / meprin and TRAF homology / TRAF-like / HECT domain / HECT, E3 ligase catalytic domain / HECT-domain (ubiquitin-transferase) / HECT domain profile. / Domain Homologous to E6-AP Carboxyl Terminus with / Ubiquitin specific protease (USP) domain signature 2. / Ubiquitin specific protease (USP) domain signature 1. / Ubiquitin specific protease, conserved site / Peptidase C19, ubiquitin carboxyl-terminal hydrolase / Ubiquitin carboxyl-terminal hydrolase / Ubiquitin associated domain / Ubiquitin specific protease domain / Ubiquitin specific protease (USP) domain profile. / Ubiquitin-associated domain / Ubiquitin-associated domain (UBA) profile. / UBA-like superfamily / Papain-like cysteine peptidase superfamily / Armadillo-type fold
Similarity search - Domain/homology
E3 ubiquitin-protein ligase HUWE1 / Ubiquitin C-terminal hydrolase 7
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.88 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

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Assembly

Deposited unit
A: E3 ubiquitin-protein ligase HUWE1
C: Ubiquitin carboxyl-terminal hydrolase 7


Theoretical massNumber of molelcules
Total (without water)610,8972
Polymers610,8972
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: 482424.406 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 carboxyl-terminal hydrolase 7 / Deubiquitinating enzyme 7 / Herpesvirus-associated ubiquitin-specific protease / Ubiquitin ...Deubiquitinating enzyme 7 / Herpesvirus-associated ubiquitin-specific protease / Ubiquitin thioesterase 7 / Ubiquitin-specific-processing protease 7


Mass: 128472.766 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: USP7, HAUSP / Production host: Homo sapiens (human) / References: UniProt: Q93009, ubiquitinyl hydrolase 1
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-USP7 complex / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
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
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 298 K

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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: 2200 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 45 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2UCSF ChimeraX1.5/v9model fitting
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.88 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 118192 / Symmetry type: POINT

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