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- EMDB-36183: Cryo-EM structure of neddylated Cul2-Rbx1-EloBC-FEM1B complexed w... -

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Entry
Database: EMDB / ID: EMD-36183
TitleCryo-EM structure of neddylated Cul2-Rbx1-EloBC-FEM1B complexed with FNIP1-FLCN
Map data
Sample
  • Complex: Neddylated Cul2-Rbx1-EloBC-FEM1B complexed with FNIP1-FLCN
    • Protein or peptide: Cullin-2CUL2
    • Protein or peptide: Elongin-B
    • Protein or peptide: Elongin-C
    • Protein or peptide: Protein fem-1 homolog B
    • Protein or peptide: Folliculin-interacting protein 1
  • Ligand: ZINC ION
KeywordsComplex / E3 ubiquitin ligase / Cullin / LIGASE
Function / homology
Function and homology information


regulation of ubiquitin-protein transferase activity / epithelial cell maturation involved in prostate gland development / positive regulation of B cell apoptotic process / negative regulation of lysosome organization / regulation of pro-B cell differentiation / branching involved in prostate gland morphogenesis / immature B cell differentiation / ATPase inhibitor activity / Amino acids regulate mTORC1 / regulation of DNA damage checkpoint ...regulation of ubiquitin-protein transferase activity / epithelial cell maturation involved in prostate gland development / positive regulation of B cell apoptotic process / negative regulation of lysosome organization / regulation of pro-B cell differentiation / branching involved in prostate gland morphogenesis / immature B cell differentiation / ATPase inhibitor activity / Amino acids regulate mTORC1 / regulation of DNA damage checkpoint / B cell apoptotic process / negative regulation of TOR signaling / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / target-directed miRNA degradation / elongin complex / VCB complex / death receptor binding / regulation of extrinsic apoptotic signaling pathway via death domain receptors / Cul5-RING ubiquitin ligase complex / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / Cul2-RING ubiquitin ligase complex / SCF ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / TOR signaling / 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 / ubiquitin-like ligase-substrate adaptor activity / enzyme activator activity / positive regulation of TOR signaling / Tat-mediated elongation of the HIV-1 transcript / 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 / positive regulation of TORC1 signaling / RNA Polymerase II Pre-transcription Events / cellular response to starvation / intrinsic apoptotic signaling pathway / B cell differentiation / transcription corepressor binding / transcription elongation by RNA polymerase II / transcription initiation at RNA polymerase II promoter / positive regulation of protein-containing complex assembly / TP53 Regulates Transcription of DNA Repair Genes / regulation of protein phosphorylation / Vif-mediated degradation of APOBEC3G / G1/S transition of mitotic cell cycle / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Inactivation of CSF3 (G-CSF) signaling / Regulation of expression of SLITs and ROBOs / ubiquitin-protein transferase activity / protein-macromolecule adaptor activity / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Antigen processing: Ubiquitination & Proteasome degradation / positive regulation of peptidyl-serine phosphorylation / Neddylation / ubiquitin-dependent protein catabolic process / protein-folding chaperone binding / proteasome-mediated ubiquitin-dependent protein catabolic process / protein-containing complex assembly / protein ubiquitination / positive regulation of protein phosphorylation / lysosomal membrane / negative regulation of cell population proliferation / apoptotic process / ubiquitin protein ligase binding / protein-containing complex binding / nucleolus / regulation of transcription by RNA polymerase II / negative regulation of transcription by RNA polymerase II / enzyme binding / nucleoplasm / metal ion binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Folliculin-interacting protein family / Folliculin-interacting protein, N-terminal domain / Folliculin-interacting protein, middle domain / Folliculin-interacting protein, C-terminal domain / Folliculin-interacting protein N-terminus / Folliculin-interacting protein middle domain / Folliculin-interacting protein C-terminus / Tripartite DENN domain, FNIP1/2-type / Tripartite DENN FNIP1/2-type domain profile. / Cullin protein neddylation domain ...Folliculin-interacting protein family / Folliculin-interacting protein, N-terminal domain / Folliculin-interacting protein, middle domain / Folliculin-interacting protein, C-terminal domain / Folliculin-interacting protein N-terminus / Folliculin-interacting protein middle domain / Folliculin-interacting protein C-terminus / Tripartite DENN domain, FNIP1/2-type / Tripartite DENN FNIP1/2-type domain profile. / Cullin protein neddylation domain / Cullin, conserved site / Cullin family signature. / Elongin B / Cullin / Elongin-C / Cullin repeat-like-containing domain superfamily / Cullin protein, neddylation domain / Cullin protein neddylation domain / Cullin / Cullin, N-terminal / Cullin homology domain / Cullin homology domain superfamily / Cullin family / Cullin family profile. / 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 / Ankyrin repeat / Ankyrin repeats (3 copies) / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily / Ubiquitin family / Ubiquitin homologues / Ubiquitin-like domain / Ubiquitin domain profile. / Ubiquitin-like domain superfamily / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
Cullin-2 / Elongin-C / Elongin-B / Folliculin-interacting protein 1 / Protein fem-1 homolog B
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.63 Å
AuthorsDai Z / Liang L / Yin YX
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81621063, 31800626 China
CitationJournal: EMBO J / Year: 2024
Title: Structural insights into the ubiquitylation strategy of the oligomeric CRL2 E3 ubiquitin ligase.
Authors: Zonglin Dai / Ling Liang / Weize Wang / Peng Zuo / Shang Yu / Yaqi Liu / Xuyang Zhao / Yishuo Lu / Yan Jin / Fangting Zhang / Dian Ding / Weiwei Deng / Yuxin Yin /
Abstract: Cullin-RING E3 ubiquitin ligase (CRL) family members play critical roles in numerous biological processes and diseases including cancer and Alzheimer's disease. Oligomerization of CRLs has been ...Cullin-RING E3 ubiquitin ligase (CRL) family members play critical roles in numerous biological processes and diseases including cancer and Alzheimer's disease. Oligomerization of CRLs has been reported to be crucial for the regulation of their activities. However, the structural basis for its regulation and mechanism of its oligomerization are not fully known. Here, we present cryo-EM structures of oligomeric CRL2 in its unneddylated state, neddylated state in complex with BEX2 as well as neddylated state in complex with FNIP1/FLCN. These structures reveal that asymmetric dimerization of N8-CRL2 is critical for the ubiquitylation of BEX2 while FNIP1/FLCN is ubiquitylated by monomeric CRL2. Our data present an example of the asymmetric homo-dimerization of CRL. Taken together, this study sheds light on the ubiquitylation strategy of oligomeric CRL2 according to substrates with different scales.
History
DepositionMay 15, 2023-
Header (metadata) releaseFeb 28, 2024-
Map releaseFeb 28, 2024-
UpdateApr 3, 2024-
Current statusApr 3, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_36183.png

Downloads & links

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Map

FileDownload / File: emd_36183.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.83 Å
Density
Contour LevelBy AUTHOR: 0.15
Minimum - Maximum-0.8469844 - 1.5057942
Average (Standard dev.)-0.0008519318 (±0.017035423)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 424.96 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_36183_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_36183_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Neddylated Cul2-Rbx1-EloBC-FEM1B complexed with FNIP1-FLCN

EntireName: Neddylated Cul2-Rbx1-EloBC-FEM1B complexed with FNIP1-FLCN
Components
  • Complex: Neddylated Cul2-Rbx1-EloBC-FEM1B complexed with FNIP1-FLCN
    • Protein or peptide: Cullin-2CUL2
    • Protein or peptide: Elongin-B
    • Protein or peptide: Elongin-C
    • Protein or peptide: Protein fem-1 homolog B
    • Protein or peptide: Folliculin-interacting protein 1
  • Ligand: ZINC ION

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Supramolecule #1: Neddylated Cul2-Rbx1-EloBC-FEM1B complexed with FNIP1-FLCN

SupramoleculeName: Neddylated Cul2-Rbx1-EloBC-FEM1B complexed with FNIP1-FLCN
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Cullin-2

MacromoleculeName: Cullin-2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 87.92782 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSLKPRVVDF DETWNKLLTT IKAVVMLEYV ERATWNDRFS DIYALCVAYP EPLGERLYTE TKIFLENHVR HLHKRVLESE EQVLVMYHR YWEEYSKGAD YMDCLYRYLN TQFIKKNKLT EADLQYGYGG VDMNEPLMEI GELALDMWRK LMVEPLQAIL I RMLLREIK ...String:
MSLKPRVVDF DETWNKLLTT IKAVVMLEYV ERATWNDRFS DIYALCVAYP EPLGERLYTE TKIFLENHVR HLHKRVLESE EQVLVMYHR YWEEYSKGAD YMDCLYRYLN TQFIKKNKLT EADLQYGYGG VDMNEPLMEI GELALDMWRK LMVEPLQAIL I RMLLREIK NDRGGEDPNQ KVIHGVINSF VHVEQYKKKF PLKFYQEIFE SPFLTETGEY YKQEASNLLQ ESNCSQYMEK VL GRLKDEE IRCRKYLHPS SYTKVIHECQ QRMVADHLQF LHAECHNIIR QEKKNDMANM YVLLRAVSTG LPHMIQELQN HIH DEGLRA TSNLTQENMP TLFVESVLEV HGKFVQLINT VLNGDQHFMS ALDKALTSVV NYREPKSVCK APELLAKYCD NLLK KSAKG MTENEVEDRL TSFITVFKYI DDKDVFQKFY ARMLAKRLIH GLSMSMDSEE AMINKLKQAC GYEFTSKLHR MYTDM SVSA DLNNKFNNFI KNQDTVIDLG ISFQIYVLQA GAWPLTQAPS STFAIPQELE KSVQMFELFY SQHFSGRKLT WLHYLC TGE VKMNYLGKPY VAMVTTYQMA VLLAFNNSET VSYKELQDST QMNEKELTKT IKSLLDVKMI NHDSEKEDID AESSFSL NM NFSSKRTKFK ITTSMQKDTP QEMEQTRSAV DEDRKMYLQA AIVRIMKARK VLRHNALIQE VISQSRARFN PSISMIKK C IEVLIDKQYI ERSQASADEY SYVAHHHHHH

UniProtKB: Cullin-2

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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: 11.748406 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MDVFLMIRRH KTTIFTDAKE SSTVFELKRI VEGILKRPPD EQRLYKDDQL LDDGKTLGEC GFTSQTARPQ APATVGLAFR ADDTFEALC IEPFSSPPEL PDVMK

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: 11.045694 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MAMYVKLISS DGHEFIVKRE HALTSGTIKA MLSGPGQFAE NETNEVNFRE IPSHVLSKVC MYFTYKVRYT NSSTEIPEFP IAPEIALEL LMAANFLDC

UniProtKB: Elongin-C

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Macromolecule #4: Protein fem-1 homolog B

MacromoleculeName: Protein fem-1 homolog B / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 70.688406 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: GEFMEGLAGY VYKAASEGKV LTLAALLLNR SESDIRYLLG YVSQQGGQRS TPLIIAARNG HAKVVRLLLE HYRVQTQQTG TVRFDGYVI DGATALWCAA GAGHFEVVKL LVSHGANVNH TTVTNSTPLR AACFDGRLDI VKYLVENNAN ISIANKYDNT C LMIAAYKG ...String:
GEFMEGLAGY VYKAASEGKV LTLAALLLNR SESDIRYLLG YVSQQGGQRS TPLIIAARNG HAKVVRLLLE HYRVQTQQTG TVRFDGYVI DGATALWCAA GAGHFEVVKL LVSHGANVNH TTVTNSTPLR AACFDGRLDI VKYLVENNAN ISIANKYDNT C LMIAAYKG HTDVVRYLLE QRADPNAKAH CGATALHFAA EAGHIDIVKE LIKWRAAIVV NGHGMTPLKV AAESCKADVV EL LLSHADC DRRSRIEALE LLGASFANDR ENYDIIKTYH YLYLAMLERF QDGDNILEKE VLPPIHAYGN RTECRNPQEL ESI RQDRDA LHMEGLIVRE RILGADNIDV SHPIIYRGAV YADNMEFEQC IKLWLHALHL RQKGNRNTHK DLLRFAQVFS QMIH LNETV KAPDIECVLR CSVLEIEQSM NRVKNISDAD VHNAMDNYEC NLYTFLYLVC ISTKTQCSEE DQCKINKQIY NLIHL DPRT REGFTLLHLA VNSNTPVDDF HTNDVCSFPN ALVTKLLLDC GAEVNAVDNE GNSALHIIVQ YNRPISDFLT LHSIII SLV EAGAHTDMTN KQNKTPLDKS TTGVSEILLK TQMKMSLKCL AARAVRANDI NYQDQIPRTL EEFVGFH

UniProtKB: Protein fem-1 homolog B

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Macromolecule #5: Folliculin-interacting protein 1

MacromoleculeName: Folliculin-interacting protein 1 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 131.499906 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAPTLFQKLF SKRTGLGAPG RDARDPDCGF SWPLPEFDPS QIRLIVYQDC ERRGRNVLFD SSVKRRNEDI SVSKLGSDAQ VKVFGKCCQ LKPGGDSSSS LDSSVTSSSD IKDQCLKYQG SRCSSDANML GEMMFGSVAM SYKGSTLKIH QIRSPPQLML S KVFTARTG ...String:
MAPTLFQKLF SKRTGLGAPG RDARDPDCGF SWPLPEFDPS QIRLIVYQDC ERRGRNVLFD SSVKRRNEDI SVSKLGSDAQ VKVFGKCCQ LKPGGDSSSS LDSSVTSSSD IKDQCLKYQG SRCSSDANML GEMMFGSVAM SYKGSTLKIH QIRSPPQLML S KVFTARTG SSICGSLNTL QDSLEFINQD NNTLKADNNT VINGLLGNIG LSQFCSPRRA FSEQGPLRLI RSASFFAVHS NP MDMPGRE LNEDRDSGIA RSASLSSLLI TPFPSPNSSL TRSCASSYQR RWRRSQTTSL ENGVFPRWSI EESFNLSDES CGP NPGIVR KKKIAIGVIF SLSKDEDENN KFNEFFFSHF PLFESHMNKL KSAIEQAMKM SRRSADASQR SLAYNRIVDA LNEF RTTIC NLYTMPRIGE PVWLTMMSGT PEKNHLCYRF MKEFTFLMEN ASKNQFLPAL ITAVLTNHLA WVPTVMPNGQ PPIKI FLEK HSSQSVDMLA KTHPYNPLWA QLGDLYGAIG SPVRLARTVV VGKRQDMVQR LLYFLTYFIR CSELQETHLL ENGEDE AIV MPGTVITTTL EKGEIEESEY VLVTMHRNKS SLLFKESEEI RTPNCNCKYC SHPLLGQNVE NISQQEREDI QNSSKEL LG ISDECQMISP SDCQEENAVD VKQYRDKLRT CFDAKLETVV CTGSVPVDKC ALSESGLEST EETWQSEKLL DSDSHTGK A MRSTGMVVEK KPPDKIVPAS FSCEAAQTKV TFLIGDSMSP DSDTELRSQA VVDQITRHHT KPLKEERGAI DQHQETKQT TKDQSGESDT QNMVSEEPCE LPCWNHSDPE SMSLFDEYFN DDSIETRTID DVPFKTSTDS KDHCCMLEFS KILCTKNNKQ NNEFCKCIE TVPQDSCKTC FPQQDQRDTL SILVPHGDKE SSDKKIAVGT EWDIPRNESS DSALGDSESE DTGHDMTRQV S SYYGGEQE DWAEEDEIPF PGSKLIEVSA VQPNIANFGR SLLGGYCSSY VPDFVLQGIG SDERFRQCLM SDLSHAVQHP VL DEPIAEA VCIIADMDKW TVQVASSQRR VTDNKLGKEV LVSSLVSNLL HSTLQLYKHN LSPNFCVMHL EDRLQELYFK SKM LSEYLR GQMRVHVKEL GVVLGIESSD LPLLAAVAST HSPYVAQILL ENLYFQ

UniProtKB: Folliculin-interacting protein 1

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Macromolecule #6: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 6 / Number of copies: 1 / 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

Concentration1.93 mg/mL
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: 2.0 µm / Nominal defocus min: 1.5 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.63 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 433719
FSC plot (resolution estimation)

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