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- EMDB-17540: Cryo-EM structure of full-length human UBR5 (homotetramer) -

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Basic information

Entry
Database: EMDB / ID: EMD-17540
TitleCryo-EM structure of full-length human UBR5 (homotetramer)
Map dataAmplitude-scaled map (LocScale).
Sample
  • Complex: Tetramer of UBR5
    • Protein or peptide: E3 ubiquitin-protein ligase UBR5
KeywordsE3 / ubiquitin ligase / HECT / LIGASE
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 / positive regulation of protein import into nucleus / protein polyubiquitination / ubiquitin protein ligase activity ...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 / positive regulation of protein import into nucleus / protein polyubiquitination / ubiquitin protein ligase activity / positive regulation of canonical Wnt signaling pathway / 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 / cytoplasm / cytosol
Similarity search - Function
: / E3 ubiquitin ligase EDD, ubiquitin-associated domain / E3 ubiquitin ligase EDD / Polyadenylate-binding protein/Hyperplastic disc protein / 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 / Poly-adenylate binding protein, unique 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(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 / Poly-adenylate binding protein, unique 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: 3.87 Å
AuthorsAguirre JD / Kater L / Kempf G / Cavadini S / Thoma NH
Funding support Switzerland, European Union, 3 items
OrganizationGrant numberCountry
Swiss National Science Foundation179541 Switzerland
Swiss National Science Foundation201206 Switzerland
European Research Council (ERC)884331European Union
CitationJournal: Mol Cell / Year: 2023
Title: UBR5 forms ligand-dependent complexes on chromatin to regulate nuclear hormone receptor stability.
Authors: Jonathan M Tsai / Jacob D Aguirre / Yen-Der Li / Jared Brown / Vivian Focht / Lukas Kater / Georg Kempf / Brittany Sandoval / Stefan Schmitt / Justine C Rutter / Pius Galli / Colby R Sandate ...Authors: Jonathan M Tsai / Jacob D Aguirre / Yen-Der Li / Jared Brown / Vivian Focht / Lukas Kater / Georg Kempf / Brittany Sandoval / Stefan Schmitt / Justine C Rutter / Pius Galli / Colby R Sandate / Jevon A Cutler / Charles Zou / Katherine A Donovan / Ryan J Lumpkin / Simone Cavadini / Paul M C Park / Quinlan Sievers / Charlie Hatton / Elizabeth Ener / Brandon D Regalado / Micah T Sperling / Mikołaj Słabicki / Jeonghyeon Kim / Rebecca Zon / Zinan Zhang / Peter G Miller / Roger Belizaire / Adam S Sperling / Eric S Fischer / Rafael Irizarry / Scott A Armstrong / Nicolas H Thomä / Benjamin L Ebert /
Abstract: Nuclear hormone receptors (NRs) are ligand-binding transcription factors that are widely targeted therapeutically. Agonist binding triggers NR activation and subsequent degradation by unknown ligand- ...Nuclear hormone receptors (NRs) are ligand-binding transcription factors that are widely targeted therapeutically. Agonist binding triggers NR activation and subsequent degradation by unknown ligand-dependent ubiquitin ligase machinery. NR degradation is critical for therapeutic efficacy in malignancies that are driven by retinoic acid and estrogen receptors. Here, we demonstrate the ubiquitin ligase UBR5 drives degradation of multiple agonist-bound NRs, including the retinoic acid receptor alpha (RARA), retinoid x receptor alpha (RXRA), glucocorticoid, estrogen, liver-X, progesterone, and vitamin D receptors. We present the high-resolution cryo-EMstructure of full-length human UBR5 and a negative stain model representing its interaction with RARA/RXRA. Agonist ligands induce sequential, mutually exclusive recruitment of nuclear coactivators (NCOAs) and UBR5 to chromatin to regulate transcriptional networks. Other pharmacological ligands such as selective estrogen receptor degraders (SERDs) degrade their receptors through differential recruitment of UBR5 or RNF111. We establish the UBR5 transcriptional regulatory hub as a common mediator and regulator of NR-induced transcription.
History
DepositionMay 31, 2023-
Header (metadata) releaseJun 14, 2023-
Map releaseJun 14, 2023-
UpdateAug 16, 2023-
Current statusAug 16, 2023Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_17540.png

Downloads & links

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Map

FileDownload / File: emd_17540.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationAmplitude-scaled map (LocScale).
Voxel sizeX=Y=Z: 1.1 Å
Density
Contour LevelBy AUTHOR: 0.0859
Minimum - Maximum-0.29378444 - 0.57892853
Average (Standard dev.)0.0021387513 (±0.015841562)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 422.40002 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Full map.

Fileemd_17540_additional_1.map
AnnotationFull map.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half-map A.

Fileemd_17540_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_17540_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 : Tetramer of UBR5

EntireName: Tetramer of UBR5
Components
  • Complex: Tetramer of UBR5
    • Protein or peptide: E3 ubiquitin-protein ligase UBR5

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Supramolecule #1: Tetramer of UBR5

SupramoleculeName: Tetramer of UBR5 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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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: 313.263688 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDYKDDDDKL AAANSSIDLI STSLYKKAGF RTMTSIHFVV HPLPGTEDQL NDRLREVSEK LNKYNLNSHP PLNVLEQATI KQCVVGPNH AAFLLEDGRV CRIGFSVQPD RLELGKPDNN DGSKLNSNSG AGRTSRPGRT SDSPWFLSGS ETLGRLAGNT L GSRWSSGV ...String:
MDYKDDDDKL AAANSSIDLI STSLYKKAGF RTMTSIHFVV HPLPGTEDQL NDRLREVSEK LNKYNLNSHP PLNVLEQATI KQCVVGPNH AAFLLEDGRV CRIGFSVQPD RLELGKPDNN DGSKLNSNSG AGRTSRPGRT SDSPWFLSGS ETLGRLAGNT L GSRWSSGV GGSGGGSSGR SSAGARDSRR QTRVIRTGRD RGSGLLGSQP QPVIPASVIP EELISQAQVV LQGKSRSVII RE LQRTNLD VNLAVNNLLS RDDEDGDDGD DTASESYLPG EDLMSLLDAD IHSAHPSVII DADAMFSEDI SYFGYPSFRR SSL SRLGSS RVLLLPLERD SELLRERESV LRLRERRWLD GASFDNERGS TSKEGEPNLD KKNTPVQSPV SLGEDLQWWP DKDG TKFIC IGALYSELLA VSSKGELYQW KWSESEPYRN AQNPSLHHPR ATFLGLTNEK IVLLSANSIR ATVATENNKV ATWVD ETLS SVASKLEHTA QTYSELQGER IVSLHCCALY TCAQLENSLY WWGVVPFSQR KKMLEKARAK NKKPKSSAGI SSMPNI TVG TQVCLRNNPL YHAGAVAFSI SAGIPKVGVL MESVWNMNDS CRFQLRSPES LKNMEKASKT TEAKPESKQE PVKTEMG PP PSPASTCSDA SSIASSASMP YKRRRSTPAP KEEEKVNEEQ WSLREVVFVE DVKNVPVGKV LKVDGAYVAV KFPGTSSN T NCQNSSGPDA DPSSLLQDCR LLRIDELQVV KTGGTPKVPD CFQRTPKKLC IPEKTEILAV NVDSKGVHAV LKTGNWVRY CIFDLATGKA EQENNFPTSS IAFLGQNERN VAIFTAGQES PIILRDGNGT IYPMAKDCMG GIRDPDWLDL PPISSLGMGV HSLINLPAN STIKKKAAVI IMAVEKQTLM QHILRCDYEA CRQYLMNLEQ AVVLEQNLQM LQTFISHRCD GNRNILHACV S VCFPTSNK ETKEEEEAER SERNTFAERL SAVEAIANAI SVVSSNGPGN RAGSSSSRSL RLREMMRRSL RAAGLGRHEA GA SSSDHQD PVSPPIAPPS WVPDPPAMDP DGDIDFILAP AVGSLTTAAT GTGQGPSTST IPGPSTEPSV VESKDRKANA HFI LKLLCD SVVLQPYLRE LLSAKDARGM TPFMSAVSGR AYPAAITILE TAQKIAKAEI SSSEKEEDVF MGMVCPSGTN PDDS PLYVL CCNDTCSFTW TGAEHINQDI FECRTCGLLE SLCCCTECAR VCHKGHDCKL KRTSPTAYCD CWEKCKCKTL IAGQK SARL DLLYRLLTAT NLVTLPNSRG EHLLLFLVQT VARQTVEHCQ YRPPRIREDR NRKTASPEDS DMPDHDLEPP RFAQLA LER VLQDWNALKS MIMFGSQENK DPLSASSRIG HLLPEEQVYL NQQSGTIRLD CFTHCLIVKC TADILLLDTL LGTLVKE LQ NKYTPGRREE AIAVTMRFLR SVARVFVILS VEMASSKKKN NFIPQPIGKC KRVFQALLPY AVEELCNVAE SLIVPVRM G IARPTAPFTL ASTSIDAMQG SEELFSVEPL PPRPSSDQSS SSSQSQSSYI IRNPQQRRIS QSQPVRGRDE EQDDIVSAD VEEVEVVEGV AGEEDHHDEQ EEHGEENAEA EGQHDEHDED GSDMELDLLA AAETESDSES NHSNQDNASG RRSVVTAATA GSEAGASSV PAFFSEDDSQ SNDSSDSDSS SSQSDDIEQE TFMLDEPLER TTNSSHANGA AQAPRSMQWA VRNTQHQRAA S TAPSSTST PAASSAGLIY IDPSNLRRSG TISTSAAAAA AALEASNASS YLTSASSLAR AYSIVIRQIS DLMGLIPKYN HL VYSQIPA AVKLTYQDAV NLQNYVEEKL IPTWNWMVSI MDSTEAQLRY GSALASAGDP GHPNHPLHAS QNSARRERMT ARE EASLRT LEGRRRATLL SARQGMMSAR GDFLNYALSL MRSHNDEHSD VLPVLDVCSL KHVAYVFQAL IYWIKAMNQQ TTLD TPQLE RKRTRELLEL GIDNEDSEHE NDDDTNQSAT LNDKDDDSLP AETGQNHPFF RRSDSMTFLG CIPPNPFEVP LAEAI PLAD QPHLLQPNAR KEDLFGRPSQ GLYSSSASSG KCLMEVTVDR NCLEVLPTKM SYAANLKNVM NMQNRQKKEG EEQPVL PEE TESSKPGPSA HDLAAQLKSS LLAEIGLTES EGPPLTSFRP QCSFMGMVIS HDMLLGRWRL SLELFGRVFM EDVGAEP GS ILTELGGFEV KESKFRREME KLRNQQSRDL SLEVDRDRDL LIQQTMRQLN NHFGRRCATT PMAVHRVKVT FKDEPGEG S GVARSFYTAI AQAFLSNEKL PNLECIQNAN KGTHTSLMQR LRNRGERDRE REREREMRRS SGLRAGSRRD RDRDFRRQL SIDTRPFRPA SEGNPSDDPE PLPAHRQALG ERLYPRVQAM QPAFASKITG MLLELSPAQL LLLLASEDSL RARVDEAMEL IIAHGRENG ADSILDLGLV DSSEKVQQEN RKRHGSSRSV VDMDLDDTDD GDDNAPLFYQ PGKRGFYTPR PGKNTEARLN C FRNIGRIL GLCLLQNELC PITLNRHVIK VLLGRKVNWH DFAFFDPVMY ESLRQLILAS QSSDADAVFS AMDLAFAIDL CK EEGGGQV ELIPNGVNIP VTPQNVYEYV RKYAEHRMLV VAEQPLHAMR KGLLDVLPKN SLEDLTAEDF RLLVNGCGEV NVQ MLISFT SFNDESGENA EKLLQFKRWF WSIVEKMSMT ERQDLVYFWT SSPSLPASEE GFQPMPSITI RPPDDQHLPT ANTC ISRLY VPLYSSKQIL KQKLLLAIKT KNFGFV

UniProtKB: E3 ubiquitin-protein ligase UBR5

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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

BufferpH: 7.6
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.87 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 393327
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-8p83:
Cryo-EM structure of full-length human UBR5 (homotetramer)

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