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- EMDB-28646: Structure of the human UBR5 HECT-type E3 ubiquitin ligase in a te... -

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Basic information

Entry
Database: EMDB / ID: EMD-28646
TitleStructure of the human UBR5 HECT-type E3 ubiquitin ligase in a tetrameric form
Map dataThe final composite map
Sample
  • Complex: Homodimer of human E3 ligase UBR5
    • Protein or peptide: E3 ubiquitin-protein ligase UBR5
  • Ligand: ZINC ION
Function / homology
Function and homology information


heterochromatin boundary formation / HECT-type E3 ubiquitin transferase / DNA repair-dependent chromatin remodeling / ubiquitin-ubiquitin ligase activity / progesterone receptor signaling pathway / protein K48-linked ubiquitination / ubiquitin binding / protein polyubiquitination / positive regulation of protein import into nucleus / positive regulation of canonical Wnt signaling pathway ...heterochromatin boundary formation / HECT-type E3 ubiquitin transferase / DNA repair-dependent chromatin remodeling / ubiquitin-ubiquitin ligase activity / progesterone receptor signaling pathway / protein K48-linked ubiquitination / ubiquitin binding / protein polyubiquitination / positive regulation of protein import into nucleus / positive regulation of canonical Wnt signaling pathway / ubiquitin protein ligase activity / DNA repair / DNA damage response / positive regulation of gene expression / perinuclear region of cytoplasm / protein-containing complex / RNA binding / zinc ion binding / nucleoplasm / membrane / nucleus / cytosol / cytoplasm
Similarity search - Function
: / E3 ubiquitin ligase EDD, ubiquitin-associated domain / E3 ubiquitin ligase EDD / Polyadenylate-binding protein/Hyperplastic disc protein / Poly-adenylate binding protein, unique domain / Poly(A)-binding protein C-terminal (PABC) domain profile. / C-terminal domain of Poly(A)-binding protein. Present also in Drosophila hyperplastics discs protein. / PABC (PABP) domain / Zinc finger, UBR-type / Zinc finger UBR-type profile. ...: / E3 ubiquitin ligase EDD, ubiquitin-associated domain / E3 ubiquitin ligase EDD / Polyadenylate-binding protein/Hyperplastic disc protein / Poly-adenylate binding protein, unique domain / Poly(A)-binding protein C-terminal (PABC) domain profile. / C-terminal domain of Poly(A)-binding protein. Present also in Drosophila hyperplastics discs protein. / PABC (PABP) domain / Zinc finger, UBR-type / Zinc finger UBR-type profile. / Putative zinc finger in N-recognin, a recognition component of the N-end rule pathway / Regulator of chromosome condensation 1/beta-lactamase-inhibitor protein II / HECT domain / HECT, E3 ligase catalytic domain / HECT-domain (ubiquitin-transferase) / HECT domain profile. / Domain Homologous to E6-AP Carboxyl Terminus with
Similarity search - Domain/homology
E3 ubiquitin-protein ligase UBR5
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsWang F / He Q / Lin G / Li H
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM131754 United States
CitationJournal: Structure / Year: 2023
Title: Structure of the human UBR5 E3 ubiquitin ligase.
Authors: Feng Wang / Qing He / Wenhu Zhan / Ziqi Yu / Efrat Finkin-Groner / Xiaojing Ma / Gang Lin / Huilin Li /
Abstract: The human UBR5 is a single polypeptide chain homology to E6AP C terminus (HECT)-type E3 ubiquitin ligase essential for embryonic development in mammals. Dysregulated UBR5 functions like an ...The human UBR5 is a single polypeptide chain homology to E6AP C terminus (HECT)-type E3 ubiquitin ligase essential for embryonic development in mammals. Dysregulated UBR5 functions like an oncoprotein to promote cancer growth and metastasis. Here, we report that UBR5 assembles into a dimer and a tetramer. Our cryoelectron microscopy (cryo-EM) structures reveal that two crescent-shaped UBR5 monomers assemble head to tail to form the dimer, and two dimers bind face to face to form the cage-like tetramer with all four catalytic HECT domains facing the central cavity. Importantly, the N-terminal region of one subunit and the HECT of the other form an "intermolecular jaw" in the dimer. We show the jaw-lining residues are important for function, suggesting that the intermolecular jaw functions to recruit ubiquitin-loaded E2 to UBR5. Further work is needed to understand how oligomerization regulates UBR5 ligase activity. This work provides a framework for structure-based anticancer drug development and contributes to a growing appreciation of E3 ligase diversity.
History
DepositionOct 23, 2022-
Header (metadata) releaseApr 19, 2023-
Map releaseApr 19, 2023-
UpdateMay 17, 2023-
Current statusMay 17, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_28646.png

Downloads & links

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Map

FileDownload / File: emd_28646.map.gz / Format: CCP4 / Size: 325 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationThe final composite map
Voxel sizeX=Y=Z: 0.828 Å
Density
Contour LevelBy AUTHOR: 0.06
Minimum - Maximum-0.0017438654 - 2.4078581
Average (Standard dev.)0.0028725183 (±0.03787649)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions440440440
Spacing440440440
CellA=B=C: 364.32 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Focused on refine map A

Fileemd_28646_additional_1.map
AnnotationFocused_on_refine_map_A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map a

Fileemd_28646_half_map_1.map
AnnotationHalf_map_a
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B

Fileemd_28646_half_map_2.map
AnnotationHalf_map_B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Homodimer of human E3 ligase UBR5

EntireName: Homodimer of human E3 ligase UBR5
Components
  • Complex: Homodimer of human E3 ligase UBR5
    • Protein or peptide: E3 ubiquitin-protein ligase UBR5
  • Ligand: ZINC ION

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Supramolecule #1: Homodimer of human E3 ligase UBR5

SupramoleculeName: Homodimer of human E3 ligase UBR5 / type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: #1 / Details: UBR5 expressed in insect cell
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 610 KDa

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Macromolecule #1: E3 ubiquitin-protein ligase UBR5

MacromoleculeName: E3 ubiquitin-protein ligase UBR5 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO / EC number: HECT-type E3 ubiquitin transferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 309.72275 KDa
Recombinant expressionOrganism: Insect cell expression vector pTIE1 (others)
SequenceString: MTSIHFVVHP LPGTEDQLND RLREVSEKLN KYNLNSHPPL NVLEQATIKQ CVVGPNHAAF LLEDGRVCRI GFSVQPDRLE LGKPDNNDG SKLNSNSGAG RTSRPGRTSD SPWFLSGSET LGRLAGNTLG SRWSSGVGGS GGGSSGRSSA GARDSRRQTR V IRTGRDRG ...String:
MTSIHFVVHP LPGTEDQLND RLREVSEKLN KYNLNSHPPL NVLEQATIKQ CVVGPNHAAF LLEDGRVCRI GFSVQPDRLE LGKPDNNDG SKLNSNSGAG RTSRPGRTSD SPWFLSGSET LGRLAGNTLG SRWSSGVGGS GGGSSGRSSA GARDSRRQTR V IRTGRDRG SGLLGSQPQP VIPASVIPEE LISQAQVVLQ GKSRSVIIRE LQRTNLDVNL AVNNLLSRDD EDGDDGDDTA SE SYLPGED LMSLLDADIH SAHPSVIIDA DAMFSEDISY FGYPSFRRSS LSRLGSSRVL LLPLERDSEL LRERESVLRL RER RWLDGA SFDNERGSTS KEGEPNLDKK NTPVQSPVSL GEDLQWWPDK DGTKFICIGA LYSELLAVSS KGELYQWKWS ESEP YRNAQ NPSLHHPRAT FLGLTNEKIV LLSANSIRAT VATENNKVAT WVDETLSSVA SKLEHTAQTY SELQGERIVS LHCCA LYTC AQLENSLYWW GVVPFSQRKK MLEKARAKNK KPKSSAGISS MPNITVGTQV CLRNNPLYHA GAVAFSISAG IPKVGV LME SVWNMNDSCR FQLRSPESLK NMEKASKTTE AKPESKQEPV KTEMGPPPSP ASTCSDASSI ASSASMPYKR RRSTPAP KE EEKVNEEQWS LREVVFVEDV KNVPVGKVLK VDGAYVAVKF PGTSSNTNCQ NSSGPDADPS SLLQDCRLLR IDELQVVK T GGTPKVPDCF QRTPKKLCIP EKTEILAVNV DSKGVHAVLK TGNWVRYCIF DLATGKAEQE NNFPTSSIAF LGQNERNVA IFTAGQESPI ILRDGNGTIY PMAKDCMGGI RDPDWLDLPP ISSLGMGVHS LINLPANSTI KKKAAVIIMA VEKQTLMQHI LRCDYEACR QYLMNLEQAV VLEQNLQMLQ TFISHRCDGN RNILHACVSV CFPTSNKETK EEEEAERSER NTFAERLSAV E AIANAISV VSSNGPGNRA GSSSSRSLRL REMMRRSLRA AGLGRHEAGA SSSDHQDPVS PPIAPPSWVP DPPAMDPDGD ID FILAPAV GSLTTAATGT GQGPSTSTIP GPSTEPSVVE SKDRKANAHF ILKLLCDSVV LQPYLRELLS AKDARGMTPF MSA VSGRAY PAAITILETA QKIAKAEISS SEKEEDVFMG MVCPSGTNPD DSPLYVLCCN DTCSFTWTGA EHINQDIFEC RTCG LLESL CCCTECARVC HKGHDCKLKR TSPTAYCDCW EKCKCKTLIA GQKSARLDLL YRLLTATNLV TLPNSRGEHL LLFLV QTVA RQTVEHCQYR PPRIREDRNR KTASPEDSDM PDHDLEPPRF AQLALERVLQ DWNALKSMIM FGSQENKDPL SASSRI GHL LPEEQVYLNQ QSGTIRLDCF THCLIVKCTA DILLLDTLLG TLVKELQNKY TPGRREEAIA VTMRFLRSVA RVFVILS VE MASSKKKNNF IPQPIGKCKR VFQALLPYAV EELCNVAESL IVPVRMGIAR PTAPFTLAST SIDAMQGSEE LFSVEPLP P RPSSDQSSSS SQSQSSYIIR NPQQRRISQS QPVRGRDEEQ DDIVSADVEE VEVVEGVAGE EDHHDEQEEH GEENAEAEG QHDEHDEDGS DMELDLLAAA ETESDSESNH SNQDNASGRR SVVTAATAGS EAGASSVPAF FSEDDSQSND SSDSDSSSSQ SDDIEQETF MLDEPLERTT NSSHANGAAQ APRSMQWAVR NTQHQRAAST APSSTSTPAA SSAGLIYIDP SNLRRSGTIS T SAAAAAAA LEASNASSYL TSASSLARAY SIVIRQISDL MGLIPKYNHL VYSQIPAAVK LTYQDAVNLQ NYVEEKLIPT WN WMVSIMD STEAQLRYGS ALASAGDPGH PNHPLHASQN SARRERMTAR EEASLRTLEG RRRATLLSAR QGMMSARGDF LNY ALSLMR SHNDEHSDVL PVLDVCSLKH VAYVFQALIY WIKAMNQQTT LDTPQLERKR TRELLELGID NEDSEHENDD DTNQ SATLN DKDDDSLPAE TGQNHPFFRR SDSMTFLGCI PPNPFEVPLA EAIPLADQPH LLQPNARKED LFGRPSQGLY SSSAS SGKC LMEVTVDRNC LEVLPTKMSY AANLKNVMNM QNRQKKEGEE QPVLPEETES SKPGPSAHDL AAQLKSSLLA EIGLTE SEG PPLTSFRPQC SFMGMVISHD MLLGRWRLSL ELFGRVFMED VGAEPGSILT ELGGFEVKES KFRREMEKLR NQQSRDL SL EVDRDRDLLI QQTMRQLNNH FGRRCATTPM AVHRVKVTFK DEPGEGSGVA RSFYTAIAQA FLSNEKLPNL ECIQNANK G THTSLMQRLR NRGERDRERE REREMRRSSG LRAGSRRDRD RDFRRQLSID TRPFRPASEG NPSDDPEPLP AHRQALGER LYPRVQAMQP AFASKITGML LELSPAQLLL LLASEDSLRA RVDEAMELII AHGRENGADS ILDLGLVDSS EKVQQENRKR HGSSRSVVD MDLDDTDDGD DNAPLFYQPG KRGFYTPRPG KNTEARLNCF RNIGRILGLC LLQNELCPIT LNRHVIKVLL G RKVNWHDF AFFDPVMYES LRQLILASQS SDADAVFSAM DLAFAIDLCK EEGGGQVELI PNGVNIPVTP QNVYEYVRKY AE HRMLVVA EQPLHAMRKG LLDVLPKNSL EDLTAEDFRL LVNGCGEVNV QMLISFTSFN DESGENAEKL LQFKRWFWSI VEK MSMTER QDLVYFWTSS PSLPASEEGF QPMPSITIRP PDDQHLPTAN TCISRLYVPL YSSKQILKQK LLLAIKTKNF GFV

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Macromolecule #2: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 2 / Number of copies: 12 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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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

Concentration0.7 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
150.0 mMNaClSodium chloridesodium chloride
25.0 mMHEPES4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
0.5 mMTECPtris(2-carboxyethyl)phosphine
GridModel: Quantifoil R2/1 / Support film - Material: GOLD / Support film - topology: CONTINUOUS
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 279 K / Instrument: FEI VITROBOT MARK IV / Details: blot 2S, blot forth 2.
Detailsfreshly purified UBR5

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 105000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
TemperatureMin: 193.0 K / Max: 193.0 K
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 65.0 e/Å2
Details: Images were collected in movie-mode at 75 frames per second
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: ANGULAR RECONSTITUTION
Final 3D classificationNumber classes: 3 / Avg.num./class: 80
Final angle assignmentType: ANGULAR RECONSTITUTION
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3.2.0) / Number images used: 401469
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: RIGID BODY FIT / Overall B value: 119 / Target criteria: Correlation coefficient
Output model

PDB-8ewi:
Structure of the human UBR5 HECT-type E3 ubiquitin ligase in a tetrameric form

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