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- EMDB-27822: Structure of the human UBR5 HECT-type E3 ubiquitin ligase in a C2... -

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Basic information

Entry
Database: EMDB / ID: EMD-27822
TitleStructure of the human UBR5 HECT-type E3 ubiquitin ligase in a C2 symmetric dimeric form
Map dataFinal 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: 2.66 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
DepositionAug 9, 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_27822.png

Downloads & links

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Map

FileDownload / File: emd_27822.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationFinal composite map
Voxel sizeX=Y=Z: 0.828 Å
Density
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.0017013521 - 2.2728834
Average (Standard dev.)0.0016999058 (±0.029294867)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 331.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Focused on refinment map of UBR5-HECT

Fileemd_27822_additional_1.map
AnnotationFocused on refinment map of UBR5-HECT
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Focused on refinment map of UBR5-NTR

Fileemd_27822_additional_2.map
AnnotationFocused on refinment map of UBR5-NTR
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: sharpen map of UBR5 in C2 symmetry

Fileemd_27822_additional_3.map
Annotationsharpen map of UBR5 in C2 symmetry
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Raw EM map of UBR5 in C2 symmetry

Fileemd_27822_additional_4.map
AnnotationRaw EM map of UBR5 in C2 symmetry
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: 2 / Enantiomer: LEVO / EC number: HECT-type E3 ubiquitin transferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 310.719719 KDa
Recombinant expressionOrganism: Insect cell expression vector pTIE1 (others)
SequenceString: DYKDDDDKMT SIHFVVHPLP GTEDQLNDRL REVSEKLNKY NLNSHPPLNV LEQATIKQCV VGPNHAAFLL EDGRVCRIGF SVQPDRLEL GKPDNNDGSK LNSNSGAGRT SRPGRTSDSP WFLSGSETLG RLAGNTLGSR WSSGVGGSGG GSSGRSSAGA R DSRRQTRV ...String:
DYKDDDDKMT SIHFVVHPLP GTEDQLNDRL REVSEKLNKY NLNSHPPLNV LEQATIKQCV VGPNHAAFLL EDGRVCRIGF SVQPDRLEL GKPDNNDGSK LNSNSGAGRT SRPGRTSDSP WFLSGSETLG RLAGNTLGSR WSSGVGGSGG GSSGRSSAGA R DSRRQTRV IRTGRDRGSG LLGSQPQPVI PASVIPEELI SQAQVVLQGK SRSVIIRELQ RTNLDVNLAV NNLLSRDDED GD DGDDTAS ESYLPGEDLM SLLDADIHSA HPSVIIDADA MFSEDISYFG YPSFRRSSLS RLGSSRVLLL PLERDSELLR ERE SVLRLR ERRWLDGASF DNERGSTSKE GEPNLDKKNT PVQSPVSLGE DLQWWPDKDG TKFICIGALY SELLAVSSKG ELYQ WKWSE SEPYRNAQNP SLHHPRATFL GLTNEKIVLL SANSIRATVA TENNKVATWV DETLSSVASK LEHTAQTYSE LQGER IVSL HCCALYTCAQ LENSLYWWGV VPFSQRKKML EKARAKNKKP KSSAGISSMP NITVGTQVCL RNNPLYHAGA VAFSIS AGI PKVGVLMESV WNMNDSCRFQ LRSPESLKNM EKASKTTEAK PESKQEPVKT EMGPPPSPAS TCSDASSIAS SASMPYK RR RSTPAPKEEE KVNEEQWSLR EVVFVEDVKN VPVGKVLKVD GAYVAVKFPG TSSNTNCQNS SGPDADPSSL LQDCRLLR I DELQVVKTGG TPKVPDCFQR TPKKLCIPEK TEILAVNVDS KGVHAVLKTG NWVRYCIFDL ATGKAEQENN FPTSSIAFL GQNERNVAIF TAGQESPIIL RDGNGTIYPM AKDCMGGIRD PDWLDLPPIS SLGMGVHSLI NLPANSTIKK KAAVIIMAVE KQTLMQHIL RCDYEACRQY LMNLEQAVVL EQNLQMLQTF ISHRCDGNRN ILHACVSVCF PTSNKETKEE EEAERSERNT F AERLSAVE AIANAISVVS SNGPGNRAGS SSSRSLRLRE MMRRSLRAAG LGRHEAGASS SDHQDPVSPP IAPPSWVPDP PA MDPDGDI DFILAPAVGS LTTAATGTGQ GPSTSTIPGP STEPSVVESK DRKANAHFIL KLLCDSVVLQ PYLRELLSAK DAR GMTPFM SAVSGRAYPA AITILETAQK IAKAEISSSE KEEDVFMGMV CPSGTNPDDS PLYVLCCNDT CSFTWTGAEH INQD IFECR TCGLLESLCC CTECARVCHK GHDCKLKRTS PTAYCDCWEK CKCKTLIAGQ KSARLDLLYR LLTATNLVTL PNSRG EHLL LFLVQTVARQ TVEHCQYRPP RIREDRNRKT ASPEDSDMPD HDLEPPRFAQ LALERVLQDW NALKSMIMFG SQENKD PLS ASSRIGHLLP EEQVYLNQQS GTIRLDCFTH CLIVKCTADI LLLDTLLGTL VKELQNKYTP GRREEAIAVT MRFLRSV AR VFVILSVEMA SSKKKNNFIP QPIGKCKRVF QALLPYAVEE LCNVAESLIV PVRMGIARPT APFTLASTSI DAMQGSEE L FSVEPLPPRP SSDQSSSSSQ SQSSYIIRNP QQRRISQSQP VRGRDEEQDD IVSADVEEVE VVEGVAGEED HHDEQEEHG EENAEAEGQH DEHDEDGSDM ELDLLAAAET ESDSESNHSN QDNASGRRSV VTAATAGSEA GASSVPAFFS EDDSQSNDSS DSDSSSSQS DDIEQETFML DEPLERTTNS SHANGAAQAP RSMQWAVRNT QHQRAASTAP SSTSTPAASS AGLIYIDPSN L RRSGTIST SAAAAAAALE ASNASSYLTS ASSLARAYSI VIRQISDLMG LIPKYNHLVY SQIPAAVKLT YQDAVNLQNY VE EKLIPTW NWMVSIMDST EAQLRYGSAL ASAGDPGHPN HPLHASQNSA RRERMTAREE ASLRTLEGRR RATLLSARQG MMS ARGDFL NYALSLMRSH NDEHSDVLPV LDVCSLKHVA YVFQALIYWI KAMNQQTTLD TPQLERKRTR ELLELGIDNE DSEH ENDDD TNQSATLNDK DDDSLPAETG QNHPFFRRSD SMTFLGCIPP NPFEVPLAEA IPLADQPHLL QPNARKEDLF GRPSQ GLYS SSASSGKCLM EVTVDRNCLE VLPTKMSYAA NLKNVMNMQN RQKKEGEEQP VLPEETESSK PGPSAHDLAA QLKSSL LAE IGLTESEGPP LTSFRPQCSF MGMVISHDML LGRWRLSLEL FGRVFMEDVG AEPGSILTEL GGFEVKESKF RREMEKL RN QQSRDLSLEV DRDRDLLIQQ TMRQLNNHFG RRCATTPMAV HRVKVTFKDE PGEGSGVARS FYTAIAQAFL SNEKLPNL E CIQNANKGTH TSLMQRLRNR GERDRERERE REMRRSSGLR AGSRRDRDRD FRRQLSIDTR PFRPASEGNP SDDPEPLPA HRQALGERLY PRVQAMQPAF ASKITGMLLE LSPAQLLLLL ASEDSLRARV DEAMELIIAH GRENGADSIL DLGLVDSSEK VQQENRKRH GSSRSVVDMD LDDTDDGDDN APLFYQPGKR GFYTPRPGKN TEARLNCFRN IGRILGLCLL QNELCPITLN R HVIKVLLG RKVNWHDFAF FDPVMYESLR QLILASQSSD ADAVFSAMDL AFAIDLCKEE GGGQVELIPN GVNIPVTPQN VY EYVRKYA EHRMLVVAEQ PLHAMRKGLL DVLPKNSLED LTAEDFRLLV NGCGEVNVQM LISFTSFNDE SGENAEKLLQ FKR WFWSIV EKMSMTERQD LVYFWTSSPS LPASEEGFQP MPSITIRPPD DQHLPTANTC ISRLYVPLYS SKQILKQKLL LAIK TKNFG FV

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Macromolecule #2: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 2 / Number of copies: 6 / 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: 2.66 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3.2.0) / Number images used: 844403

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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-8e0q:
Structure of the human UBR5 HECT-type E3 ubiquitin ligase in a C2 symmetric dimeric form

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