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- EMDB-17713: Catalytic module of human CTLH E3 ligase bound to multiphosphoryl... -

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Entry
Database: EMDB / ID: EMD-17713
TitleCatalytic module of human CTLH E3 ligase bound to multiphosphorylated UBE2H~ubiquitin
Map data
Sample
  • Complex: Complex of human CTLHSR4 E3 ligase bound to engineered ARMC8-specific VH and multiphosphorylated UBE2H~ubiquitin
    • Protein or peptide: E3 ubiquitin-protein transferase RMND5A
    • Protein or peptide: Ubiquitin-conjugating enzyme E2 H
    • Protein or peptide: E3 ubiquitin-protein transferase MAEA
    • Protein or peptide: Ubiquitin
  • Ligand: ZINC ION
KeywordsE3 ubiquitin ligase / E2 ubiquitin-conjugating enzyme / phosphorylation / CTLH / GID / UBE2H / LIGASE
Function / homology
Function and homology information


GID complex / enucleate erythrocyte development / actomyosin contractile ring / (E3-independent) E2 ubiquitin-conjugating enzyme / negative regulation of myeloid cell apoptotic process / protein K11-linked ubiquitination / E2 ubiquitin-conjugating enzyme / ubiquitin conjugating enzyme activity / erythrocyte maturation / protein K48-linked ubiquitination ...GID complex / enucleate erythrocyte development / actomyosin contractile ring / (E3-independent) E2 ubiquitin-conjugating enzyme / negative regulation of myeloid cell apoptotic process / protein K11-linked ubiquitination / E2 ubiquitin-conjugating enzyme / ubiquitin conjugating enzyme activity / erythrocyte maturation / protein K48-linked ubiquitination / ubiquitin ligase complex / cytoskeleton organization / Maturation of protein E / Maturation of protein E / ER Quality Control Compartment (ERQC) / Myoclonic epilepsy of Lafora / FLT3 signaling by CBL mutants / Prevention of phagosomal-lysosomal fusion / 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 / Membrane binding and targetting of GAG proteins / Constitutive Signaling by NOTCH1 HD Domain Mutants / Endosomal Sorting Complex Required For Transport (ESCRT) / NOTCH2 Activation and Transmission of Signal to the Nucleus / IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / Negative regulation of FLT3 / Regulation of FZD by ubiquitination / TICAM1,TRAF6-dependent induction of TAK1 complex / TICAM1-dependent activation of IRF3/IRF7 / APC/C:Cdc20 mediated degradation of Cyclin B / regulation of mitotic cell cycle / Downregulation of ERBB4 signaling / p75NTR recruits signalling complexes / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / APC-Cdc20 mediated degradation of Nek2A / PINK1-PRKN Mediated Mitophagy / TRAF6-mediated induction of TAK1 complex within TLR4 complex / InlA-mediated entry of Listeria monocytogenes into host cells / Pexophagy / Regulation of innate immune responses to cytosolic DNA / VLDLR internalisation and degradation / Downregulation of ERBB2:ERBB3 signaling / NRIF signals cell death from the nucleus / Activated NOTCH1 Transmits Signal to the Nucleus / Translesion synthesis by REV1 / NF-kB is activated and signals survival / Regulation of PTEN localization / Translesion synthesis by POLK / Regulation of BACH1 activity / Synthesis of active ubiquitin: roles of E1 and E2 enzymes / Translesion synthesis by POLI / Gap-filling DNA repair synthesis and ligation in GG-NER / MAP3K8 (TPL2)-dependent MAPK1/3 activation / TICAM1, RIP1-mediated IKK complex recruitment / Downregulation of TGF-beta receptor signaling / Josephin domain DUBs / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / Regulation of activated PAK-2p34 by proteasome mediated degradation / InlB-mediated entry of Listeria monocytogenes into host cell / IKK complex recruitment mediated by RIP1 / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / Autodegradation of Cdh1 by Cdh1:APC/C / TNFR1-induced NF-kappa-B signaling pathway / APC/C:Cdc20 mediated degradation of Securin / Asymmetric localization of PCP proteins / TCF dependent signaling in response to WNT / SCF-beta-TrCP mediated degradation of Emi1 / Regulation of NF-kappa B signaling / NIK-->noncanonical NF-kB signaling / Ubiquitin-dependent degradation of Cyclin D / AUF1 (hnRNP D0) binds and destabilizes mRNA / Negative regulators of DDX58/IFIH1 signaling / TNFR2 non-canonical NF-kB pathway / NOTCH3 Activation and Transmission of Signal to the Nucleus / activated TAK1 mediates p38 MAPK activation / Assembly of the pre-replicative complex / Vpu mediated degradation of CD4 / Deactivation of the beta-catenin transactivating complex / Degradation of DVL / Ubiquitin Mediated Degradation of Phosphorylated Cdc25A / Recognition of DNA damage by PCNA-containing replication complex / Regulation of signaling by CBL / Dectin-1 mediated noncanonical NF-kB signaling / Hh mutants are degraded by ERAD / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / Fanconi Anemia Pathway / Negative regulation of FGFR3 signaling / Termination of translesion DNA synthesis / Peroxisomal protein import / Degradation of AXIN / Downregulation of SMAD2/3:SMAD4 transcriptional activity / Regulation of TNFR1 signaling / Defective CFTR causes cystic fibrosis / Degradation of GLI1 by the proteasome
Similarity search - Function
Protein RMD5 homologue A, degenerated RING finger / Fyv10 family / Gid-type RING finger domain / Gid-type RING finger profile. / CRA domain / CT11-RanBPM / CTLH/CRA C-terminal to LisH motif domain / CTLH/CRA C-terminal to LisH motif domain / C-terminal to LisH motif. / CTLH, C-terminal LisH motif ...Protein RMD5 homologue A, degenerated RING finger / Fyv10 family / Gid-type RING finger domain / Gid-type RING finger profile. / CRA domain / CT11-RanBPM / CTLH/CRA C-terminal to LisH motif domain / CTLH/CRA C-terminal to LisH motif domain / C-terminal to LisH motif. / CTLH, C-terminal LisH motif / C-terminal to LisH (CTLH) motif profile. / Zinc finger, RING-type, eukaryotic / RING-type zinc-finger / Lissencephaly type-1-like homology motif / LIS1 homology (LisH) motif profile. / LIS1 homology motif / Ubiquitin-conjugating enzyme, active site / Ubiquitin-conjugating (UBC) active site signature. / Ubiquitin-conjugating enzyme E2, catalytic domain homologues / Ubiquitin-conjugating enzyme E2 / Ubiquitin-conjugating enzyme / Ubiquitin-conjugating (UBC) core domain profile. / Ubiquitin-conjugating enzyme/RWD-like / Ubiquitin conserved site / Ubiquitin domain / Ubiquitin domain signature. / Ubiquitin family / Ubiquitin homologues / Ubiquitin-like domain / Ubiquitin domain profile. / Ubiquitin-like domain superfamily
Similarity search - Domain/homology
Polyubiquitin-C / Ubiquitin-conjugating enzyme E2 H / E3 ubiquitin-protein transferase MAEA / E3 ubiquitin-protein transferase RMND5A
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsChrustowicz J / Sherpa D / Prabu RJ / Schulman BA
Funding support Germany, European Union, 3 items
OrganizationGrant numberCountry
Max Planck Society Germany
European Research Council (ERC)H2020 789016-NEDD8ActivateEuropean Union
German Research Foundation (DFG)SCHU 3196/1-1 Germany
CitationJournal: Mol Cell / Year: 2024
Title: Multisite phosphorylation dictates selective E2-E3 pairing as revealed by Ubc8/UBE2H-GID/CTLH assemblies.
Authors: Jakub Chrustowicz / Dawafuti Sherpa / Jerry Li / Christine R Langlois / Eleftheria C Papadopoulou / D Tung Vu / Laura A Hehl / Özge Karayel / Viola Beier / Susanne von Gronau / Judith ...Authors: Jakub Chrustowicz / Dawafuti Sherpa / Jerry Li / Christine R Langlois / Eleftheria C Papadopoulou / D Tung Vu / Laura A Hehl / Özge Karayel / Viola Beier / Susanne von Gronau / Judith Müller / J Rajan Prabu / Matthias Mann / Gary Kleiger / Arno F Alpi / Brenda A Schulman /
Abstract: Ubiquitylation is catalyzed by coordinated actions of E3 and E2 enzymes. Molecular principles governing many important E3-E2 partnerships remain unknown, including those for RING-family GID/CTLH E3 ...Ubiquitylation is catalyzed by coordinated actions of E3 and E2 enzymes. Molecular principles governing many important E3-E2 partnerships remain unknown, including those for RING-family GID/CTLH E3 ubiquitin ligases and their dedicated E2, Ubc8/UBE2H (yeast/human nomenclature). GID/CTLH-Ubc8/UBE2H-mediated ubiquitylation regulates biological processes ranging from yeast metabolic signaling to human development. Here, cryoelectron microscopy (cryo-EM), biochemistry, and cell biology reveal this exquisitely specific E3-E2 pairing through an unconventional catalytic assembly and auxiliary interactions 70-100 Å away, mediated by E2 multisite phosphorylation. Rather than dynamic polyelectrostatic interactions reported for other ubiquitylation complexes, multiple Ubc8/UBE2H phosphorylation sites within acidic CK2-targeted sequences specifically anchor the E2 C termini to E3 basic patches. Positions of phospho-dependent interactions relative to the catalytic domains correlate across evolution. Overall, our data show that phosphorylation-dependent multivalency establishes a specific E3-E2 partnership, is antagonistic with dephosphorylation, rigidifies the catalytic centers within a flexing GID E3-substrate assembly, and facilitates substrate collision with ubiquitylation active sites.
History
DepositionJun 23, 2023-
Header (metadata) releaseJan 3, 2024-
Map releaseJan 3, 2024-
UpdateJan 31, 2024-
Current statusJan 31, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_17713.png

Downloads & links

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Map

FileDownload / File: emd_17713.map.gz / Format: CCP4 / Size: 76.8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.851 Å
Density
Contour LevelBy AUTHOR: 0.00671
Minimum - Maximum-0.021862298 - 0.037438527
Average (Standard dev.)0.000026347185 (±0.0008517561)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions272272272
Spacing272272272
CellA=B=C: 231.472 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_17713_msk_1.map
Projections & Slices
AxesZYX

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Additional map: #1

Fileemd_17713_additional_1.map
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Half map: #2

Fileemd_17713_half_map_1.map
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Half map: #1

Fileemd_17713_half_map_2.map
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Sample components

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Entire : Complex of human CTLHSR4 E3 ligase bound to engineered ARMC8-spec...

EntireName: Complex of human CTLHSR4 E3 ligase bound to engineered ARMC8-specific VH and multiphosphorylated UBE2H~ubiquitin
Components
  • Complex: Complex of human CTLHSR4 E3 ligase bound to engineered ARMC8-specific VH and multiphosphorylated UBE2H~ubiquitin
    • Protein or peptide: E3 ubiquitin-protein transferase RMND5A
    • Protein or peptide: Ubiquitin-conjugating enzyme E2 H
    • Protein or peptide: E3 ubiquitin-protein transferase MAEA
    • Protein or peptide: Ubiquitin
  • Ligand: ZINC ION

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Supramolecule #1: Complex of human CTLHSR4 E3 ligase bound to engineered ARMC8-spec...

SupramoleculeName: Complex of human CTLHSR4 E3 ligase bound to engineered ARMC8-specific VH and multiphosphorylated UBE2H~ubiquitin
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Details: Map obtained by focus refinement over the catalytic module (RMND5A, MAEA) and UBE2H~ubiquitin
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 600 KDa

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Macromolecule #1: E3 ubiquitin-protein transferase RMND5A

MacromoleculeName: E3 ubiquitin-protein transferase RMND5A / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: RING-type E3 ubiquitin transferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 44.043449 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MDQCVTVERE LEKVLHKFSG YGQLCERGLE ELIDYTGGLK HEILQSHGQD AELSGTLSLV LTQCCKRIKD TVQKLASDHK DIHSSVSRV GKAIDKNFDS DISSVGIDGC WQADSQRLLN EVMVEHFFRQ GMLDVAEELC QESGLSVDPS QKEPFVELNR I LEALKVRV ...String:
MDQCVTVERE LEKVLHKFSG YGQLCERGLE ELIDYTGGLK HEILQSHGQD AELSGTLSLV LTQCCKRIKD TVQKLASDHK DIHSSVSRV GKAIDKNFDS DISSVGIDGC WQADSQRLLN EVMVEHFFRQ GMLDVAEELC QESGLSVDPS QKEPFVELNR I LEALKVRV LRPALEWAVS NREMLIAQNS SLEFKLHRLY FISLLMGGTT NQREALQYAK NFQPFALNHQ KDIQVLMGSL VY LRQGIEN SPYVHLLDAN QWADICDIFT RDACALLGLS VESPLSVSFS AGCVALPALI NIKAVIEQRQ CTGVWNQKDE LPI EVDLGK KCWYHSIFAC PILRQQTTDN NPPMKLVCGH IISRDALNKM FNGSKLKCPY CPMEQSPGDA KQIFF

UniProtKB: E3 ubiquitin-protein transferase RMND5A

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Macromolecule #2: Ubiquitin-conjugating enzyme E2 H

MacromoleculeName: Ubiquitin-conjugating enzyme E2 H / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: E2 ubiquitin-conjugating enzyme
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 21.260986 KDa
Recombinant expressionOrganism: Trichoplusia (butterflies/moths)
SequenceString: MSSPSPGKRR MDTDVVKLIE SKHEVTILGG LNEFVVKFYG PQGTPYEGGV WKVRVDLPDK YPFKSPSIGF MNKIFHPNID EASGTVKLD VINQTWTALY DLTNIFESFL PQLLAYPNPI DPLNGDAAAM YLHRPEEYKQ KIKEYIQKYA TEEALKEQEE G TGD(SEP)(SEP) ...String:
MSSPSPGKRR MDTDVVKLIE SKHEVTILGG LNEFVVKFYG PQGTPYEGGV WKVRVDLPDK YPFKSPSIGF MNKIFHPNID EASGTVKLD VINQTWTALY DLTNIFESFL PQLLAYPNPI DPLNGDAAAM YLHRPEEYKQ KIKEYIQKYA TEEALKEQEE G TGD(SEP)(SEP)(SEP)E(SEP) (SEP)M(SEP)DF(SEP)EDEA QDMEL

UniProtKB: Ubiquitin-conjugating enzyme E2 H

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Macromolecule #3: E3 ubiquitin-protein transferase MAEA

MacromoleculeName: E3 ubiquitin-protein transferase MAEA / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO / EC number: RING-type E3 ubiquitin transferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 45.356332 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MAVQESAAQL SMTLKVQEYP TLKVPYETLN KRFRAAQKNI DRETSHVTMV VAELEKTLSG CPAVDSVVSL LDGVVEKLSV LKRKAVESI QAEDESAKLC KRRIEHLKEH SSDQPAAASV WKRKRMDRMM VEHLLRCGYY NTAVKLARQS GIEDLVNIEM F LTAKEVEE ...String:
MAVQESAAQL SMTLKVQEYP TLKVPYETLN KRFRAAQKNI DRETSHVTMV VAELEKTLSG CPAVDSVVSL LDGVVEKLSV LKRKAVESI QAEDESAKLC KRRIEHLKEH SSDQPAAASV WKRKRMDRMM VEHLLRCGYY NTAVKLARQS GIEDLVNIEM F LTAKEVEE SLERRETATC LAWCHDNKSR LRKMKSCLEF SLRIQEFIEL IRQNKRLDAV RHARKHFSQA EGSQLDEVRQ AM GMLAFPP DTHISPYKDL LDPARWRMLI QQFRYDNYRL HQLGNNSVFT LTLQAGLSAI KTPQCYKEDG SSKSPDCPVC SRS LNKLAQ PLPMAHCANS RLVCKISGDV MNENNPPMML PNGYVYGYNS LLSIRQDDKV VCPRTKEVFH FSQAEKVYIM

UniProtKB: E3 ubiquitin-protein transferase MAEA

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Macromolecule #4: Ubiquitin

MacromoleculeName: Ubiquitin / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 8.576831 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MQIFVKTLTG KTITLEVEPS DTIENVKAKI QDKEGIPPDQ QRLIFAGKQL EDGRTLSDYN IQKESTLHLV LRLRGG

UniProtKB: Polyubiquitin-C

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Macromolecule #5: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 5 / Number of copies: 2 / 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

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.3000000000000003 µm / Nominal defocus min: 0.8 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 68.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

12537

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 45472
FSC plot (resolution estimation)

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