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- EMDB-46645: Focused map of Cryo-EM structure of Ubiquitin C-degron bound to K... -

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Basic information

Entry
Database: EMDB / ID: EMD-46645
TitleFocused map of Cryo-EM structure of Ubiquitin C-degron bound to KLHDC10-EloB/C
Map data
Sample
  • Complex: Trapped ARIH1-diUB-CRL2-KLHDC10 complex
    • Protein or peptide: Kelch domain-containing protein 10
    • Protein or peptide: Elongin-B
    • Protein or peptide: Elongin-C
    • Protein or peptide: Ubiquitin-C
KeywordsKLHDC10 / ubiquitin / E3 / Cullin-RING / C-Degron / LIGASE
Function / homology
Function and homology information


positive regulation of stress-activated MAPK cascade / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / target-directed miRNA degradation / VCB complex / elongin complex / Cul5-RING ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / HIV elongation arrest and recovery ...positive regulation of stress-activated MAPK cascade / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / target-directed miRNA degradation / VCB complex / elongin complex / Cul5-RING ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / Tat-mediated elongation of the HIV-1 transcript / ubiquitin-like ligase-substrate adaptor activity / Formation of HIV-1 elongation complex containing HIV-1 Tat / Formation of HIV elongation complex in the absence of HIV Tat / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / Maturation of protein E / Maturation of protein E / RNA Polymerase II Pre-transcription Events / ER Quality Control Compartment (ERQC) / rescue of stalled ribosome / 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 / Endosomal Sorting Complex Required For Transport (ESCRT) / Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7 / Negative regulation of FLT3 / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / Constitutive Signaling by NOTCH1 HD Domain Mutants / Regulation of TBK1, IKKε-mediated activation of IRF3, IRF7 upon TLR3 ligation / IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation / NOTCH2 Activation and Transmission of Signal to the Nucleus / TICAM1,TRAF6-dependent induction of TAK1 complex / TICAM1-dependent activation of IRF3/IRF7 / APC/C:Cdc20 mediated degradation of Cyclin B / Regulation of FZD by ubiquitination / Downregulation of ERBB4 signaling / p75NTR recruits signalling complexes / APC-Cdc20 mediated degradation of Nek2A / InlA-mediated entry of Listeria monocytogenes into host cells / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / TRAF6-mediated induction of TAK1 complex within TLR4 complex / Regulation of pyruvate metabolism / Regulation of innate immune responses to cytosolic DNA / NF-kB is activated and signals survival / Downregulation of ERBB2:ERBB3 signaling / Pexophagy / NRIF signals cell death from the nucleus / Regulation of PTEN localization / VLDLR internalisation and degradation / Activated NOTCH1 Transmits Signal to the Nucleus / Synthesis of active ubiquitin: roles of E1 and E2 enzymes / Regulation of BACH1 activity / MAP3K8 (TPL2)-dependent MAPK1/3 activation / TICAM1, RIP1-mediated IKK complex recruitment / Translesion synthesis by REV1 / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / Translesion synthesis by POLK / InlB-mediated entry of Listeria monocytogenes into host cell / Downregulation of TGF-beta receptor signaling / Josephin domain DUBs / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / Regulation of activated PAK-2p34 by proteasome mediated degradation / Translesion synthesis by POLI / IKK complex recruitment mediated by RIP1 / Gap-filling DNA repair synthesis and ligation in GG-NER / transcription corepressor binding / PINK1-PRKN Mediated Mitophagy / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / TNFR1-induced NF-kappa-B signaling pathway / Autodegradation of Cdh1 by Cdh1:APC/C / APC/C:Cdc20 mediated degradation of Securin / TCF dependent signaling in response to WNT / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / Regulation of NF-kappa B signaling / Asymmetric localization of PCP proteins / Ubiquitin-dependent degradation of Cyclin D / SCF-beta-TrCP mediated degradation of Emi1 / NIK-->noncanonical NF-kB signaling / activated TAK1 mediates p38 MAPK activation / Negative regulators of DDX58/IFIH1 signaling / TNFR2 non-canonical NF-kB pathway / AUF1 (hnRNP D0) binds and destabilizes mRNA / TP53 Regulates Transcription of DNA Repair Genes / transcription initiation at RNA polymerase II promoter / Regulation of signaling by CBL / NOTCH3 Activation and Transmission of Signal to the Nucleus / Vpu mediated degradation of CD4 / Assembly of the pre-replicative complex / Ubiquitin Mediated Degradation of Phosphorylated Cdc25A / Degradation of DVL / Deactivation of the beta-catenin transactivating complex / Negative regulation of FGFR3 signaling
Similarity search - Function
: / Kelch motif / Host cell factor, Kelch-repeats domain / Galactose oxidase, central domain / Kelch / Kelch repeat type 1 / Elongin-C / Elongin B / Kelch-type beta propeller / S-phase kinase-associated protein 1-like ...: / Kelch motif / Host cell factor, Kelch-repeats domain / Galactose oxidase, central domain / Kelch / Kelch repeat type 1 / Elongin-C / Elongin B / Kelch-type beta propeller / S-phase kinase-associated protein 1-like / SKP1 component, POZ domain / Skp1 family, tetramerisation domain / Found in Skp1 protein family / SKP1/BTB/POZ domain superfamily / : / Ubiquitin domain signature. / Ubiquitin conserved site / Ubiquitin domain / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Ubiquitin-like domain superfamily
Similarity search - Domain/homology
Polyubiquitin-C / Elongin-C / Elongin-B / Kelch domain-containing protein 10
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsChittori S / Scott DC / Schulman BA
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)5R01CA247365 United States
CitationJournal: Nat Commun / Year: 2024
Title: Structural basis for C-degron selectivity across KLHDCX family E3 ubiquitin ligases.
Authors: Daniel C Scott / Sagar Chittori / Nicholas Purser / Moeko T King / Samuel A Maiwald / Kelly Churion / Amanda Nourse / Chan Lee / Joao A Paulo / Darcie J Miller / Stephen J Elledge / J Wade ...Authors: Daniel C Scott / Sagar Chittori / Nicholas Purser / Moeko T King / Samuel A Maiwald / Kelly Churion / Amanda Nourse / Chan Lee / Joao A Paulo / Darcie J Miller / Stephen J Elledge / J Wade Harper / Gary Kleiger / Brenda A Schulman /
Abstract: Specificity of the ubiquitin-proteasome system depends on E3 ligase-substrate interactions. Many such pairings depend on E3 ligases binding to peptide-like sequences - termed N- or C-degrons - at the ...Specificity of the ubiquitin-proteasome system depends on E3 ligase-substrate interactions. Many such pairings depend on E3 ligases binding to peptide-like sequences - termed N- or C-degrons - at the termini of substrates. However, our knowledge of structural features distinguishing closely related C-degron substrate-E3 pairings is limited. Here, by systematically comparing ubiquitylation activities towards a suite of common model substrates, and defining interactions by biochemistry, crystallography, and cryo-EM, we reveal principles of C-degron recognition across the KLHDCX family of Cullin-RING ligases (CRLs). First, a motif common across these E3 ligases anchors a substrate's C-terminus. However, distinct locations of this C-terminus anchor motif in different blades of the KLHDC2, KLHDC3, and KLHDC10 β-propellers establishes distinct relative positioning and molecular environments for substrate C-termini. Second, our structural data show KLHDC3 has a pre-formed pocket establishing preference for an Arg or Gln preceding a C-terminal Gly, whereas conformational malleability contributes to KLHDC10's recognition of varying features adjacent to substrate C-termini. Finally, additional non-consensus interactions, mediated by C-degron binding grooves and/or by distal propeller surfaces and substrate globular domains, can substantially impact substrate binding and ubiquitylatability. Overall, the data reveal combinatorial mechanisms determining specificity and plasticity of substrate recognition by KLDCX-family C-degron E3 ligases.
History
DepositionAug 19, 2024-
Header (metadata) releaseNov 20, 2024-
Map releaseNov 20, 2024-
UpdateFeb 5, 2025-
Current statusFeb 5, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_46645.png

Downloads & links

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Map

FileDownload / File: emd_46645.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.3 Å/pix.
x 360 pix.
= 466.92 Å		1.3 Å/pix.
x 360 pix.
= 466.92 Å		1.3 Å/pix.
x 360 pix.
= 466.92 Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.297 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.202
Minimum - Maximum-0.48354346 - 1.1814079
Average (Standard dev.)-0.0007011356 (±0.010655936)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 466.92 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_46645_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_46645_half_map_2.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : Trapped ARIH1-diUB-CRL2-KLHDC10 complex

EntireName: Trapped ARIH1-diUB-CRL2-KLHDC10 complex
Components
  • Complex: Trapped ARIH1-diUB-CRL2-KLHDC10 complex
    • Protein or peptide: Kelch domain-containing protein 10
    • Protein or peptide: Elongin-B
    • Protein or peptide: Elongin-C
    • Protein or peptide: Ubiquitin-C

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Supramolecule #1: Trapped ARIH1-diUB-CRL2-KLHDC10 complex

SupramoleculeName: Trapped ARIH1-diUB-CRL2-KLHDC10 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all

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Macromolecule #1: Kelch domain-containing protein 10

MacromoleculeName: Kelch domain-containing protein 10 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 45.745375 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: QLNRFVQLSG RPHLPGKKKI RWDPVRRRFI QSCPIIRIPN RFLRGHRPPP ARSGHRCVAD NTNLYVFGGY NPDYDESGGP DNEDYPLFR ELWRYHFATG VWHQMGTDGY MPRELASMSL VLHGNNLLVF GGTGIPFGES NGNDVHVCNV KYKRWALLSC R GKKPSRIY ...String:
QLNRFVQLSG RPHLPGKKKI RWDPVRRRFI QSCPIIRIPN RFLRGHRPPP ARSGHRCVAD NTNLYVFGGY NPDYDESGGP DNEDYPLFR ELWRYHFATG VWHQMGTDGY MPRELASMSL VLHGNNLLVF GGTGIPFGES NGNDVHVCNV KYKRWALLSC R GKKPSRIY GQAMAIINGS LYVFGGTTGY IYSTDLHKLD LNTREWTQLK PNNLSCDLPE ERYRHEIAHD GQRIYILGGG TS WTAYSLN KIHAYNLETN AWEEIATKPH EKIGFPAARR CHSCVQIKND VFICGGYNGE VILGDIWKLN LQTFQWVKLP ATM PEPVYF HCAAVTPAGC MYIHGGVVNI HENKRTGSLF KIWLVVPSLL ELAWEKLLAA FPNLANLSRT QLLHLGLTQG LIER LK

UniProtKB: Kelch domain-containing protein 10

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Macromolecule #2: Elongin-B

MacromoleculeName: Elongin-B / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.147781 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString:
MDVFLMIRRH KTTIFTDAKE SSTVFELKRI VEGILKRPPD EQRLYKDDQL LDDGKTLGEC GFTSQTARPQ APATVGLAFR ADDTFEALC IEPFSSPPEL PDVMKPQDSG SSANEQAVQ

UniProtKB: Elongin-B

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Macromolecule #3: Elongin-C

MacromoleculeName: Elongin-C / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 12.485135 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString:
MDGEEKTYGG CEGPDAMYVK LISSDGHEFI VKREHALTSG TIKAMLSGPG QFAENETNEV NFREIPSHVL SKVCMYFTYK VRYTNSSTE IPEFPIAPEI ALELLMAANF LDC

UniProtKB: Elongin-C

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Macromolecule #4: Ubiquitin-C

MacromoleculeName: Ubiquitin-C / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 8.550794 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MQIFVKTLTG KTITLEVEPS DTIENVKAKI QDKEGIPPDQ QRLIFAGCQL EDGRTLSDYN IQKESTLHLV LRLRGG

UniProtKB: Polyubiquitin-C

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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

Concentration0.8 mg/mL
BufferpH: 7.5
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number real images: 13395 / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.25 µm / Nominal defocus min: 0.6 µm / Nominal magnification: 130000
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 234648
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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