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- EMDB-37752: Structure of the DDB1-AMBRA1 E3 ligase receptor complex linked to... -

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Basic information

Entry
Database: EMDB / ID: EMD-37752
TitleStructure of the DDB1-AMBRA1 E3 ligase receptor complex linked to cell cycle regulation
Map data
Sample
  • Complex: DDB1-AMBRA1 complex
    • Protein or peptide: Activating molecule in BECN1-regulated autophagy protein 1
    • Protein or peptide: DNA damage-binding protein 1
KeywordsE3 ligase / STRUCTURAL PROTEIN
Function / homology
Function and homology information


positive regulation of free ubiquitin chain polymerization / response to mitochondrial depolarisation / positive regulation of mitophagy / positive regulation by virus of viral protein levels in host cell / spindle assembly involved in female meiosis / epigenetic programming in the zygotic pronuclei / positive regulation of regulatory T cell differentiation / Cul4-RING E3 ubiquitin ligase complex / UV-damage excision repair / neural tube development ...positive regulation of free ubiquitin chain polymerization / response to mitochondrial depolarisation / positive regulation of mitophagy / positive regulation by virus of viral protein levels in host cell / spindle assembly involved in female meiosis / epigenetic programming in the zygotic pronuclei / positive regulation of regulatory T cell differentiation / Cul4-RING E3 ubiquitin ligase complex / UV-damage excision repair / neural tube development / biological process involved in interaction with symbiont / regulation of mitotic cell cycle phase transition / WD40-repeat domain binding / Cul4A-RING E3 ubiquitin ligase complex / negative regulation of cardiac muscle cell apoptotic process / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / Macroautophagy / negative regulation of reproductive process / negative regulation of developmental process / regulation of G1/S transition of mitotic cell cycle / viral release from host cell / axoneme / cullin family protein binding / ectopic germ cell programmed cell death / autophagosome assembly / mitophagy / ubiquitin-like ligase-substrate adaptor activity / proteasomal protein catabolic process / positive regulation of viral genome replication / phagocytic vesicle / positive regulation of autophagy / : / positive regulation of gluconeogenesis / autophagosome / cellular response to starvation / nucleotide-excision repair / Recognition of DNA damage by PCNA-containing replication complex / DNA Damage Recognition in GG-NER / regulation of circadian rhythm / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / Dual Incision in GG-NER / Wnt signaling pathway / Formation of Incision Complex in GG-NER / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / protein polyubiquitination / positive regulation of protein catabolic process / cellular response to UV / rhythmic process / GTPase binding / site of double-strand break / Neddylation / protein-macromolecule adaptor activity / ubiquitin-dependent protein catabolic process / protein phosphatase binding / proteasome-mediated ubiquitin-dependent protein catabolic process / negative regulation of neuron apoptotic process / mitochondrial outer membrane / damaged DNA binding / chromosome, telomeric region / cell differentiation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / cytoskeleton / protein ubiquitination / negative regulation of cell population proliferation / intracellular membrane-bounded organelle / focal adhesion / DNA repair / DNA damage response / ubiquitin protein ligase binding / protein-containing complex binding / negative regulation of apoptotic process / regulation of transcription by RNA polymerase II / nucleolus / apoptotic process / perinuclear region of cytoplasm / endoplasmic reticulum / protein-containing complex / mitochondrion / DNA binding / extracellular space / extracellular exosome / nucleoplasm / nucleus / cytosol / cytoplasm
Similarity search - Function
: / Cleavage/polyadenylation specificity factor, A subunit, N-terminal / Mono-functional DNA-alkylating methyl methanesulfonate N-term / Cleavage/polyadenylation specificity factor, A subunit, C-terminal / : / CPSF A subunit region / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. ...: / Cleavage/polyadenylation specificity factor, A subunit, N-terminal / Mono-functional DNA-alkylating methyl methanesulfonate N-term / Cleavage/polyadenylation specificity factor, A subunit, C-terminal / : / CPSF A subunit region / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
DNA damage-binding protein 1 / Activating molecule in BECN1-regulated autophagy protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.08 Å
AuthorsLiu M / Wang Y / Su MY / Stjepanovic G
Funding support China, 1 items
OrganizationGrant numberCountry
Other government2022A1515010856 China
CitationJournal: Nat Commun / Year: 2023
Title: Structure of the DDB1-AMBRA1 E3 ligase receptor complex linked to cell cycle regulation.
Authors: Ming Liu / Yang Wang / Fei Teng / Xinyi Mai / Xi Wang / Ming-Yuan Su / Goran Stjepanovic /
Abstract: AMBRA1 is a tumor suppressor protein that functions as a substrate receptor of the ubiquitin conjugation system with roles in autophagy and the cell cycle regulatory network. The intrinsic disorder ...AMBRA1 is a tumor suppressor protein that functions as a substrate receptor of the ubiquitin conjugation system with roles in autophagy and the cell cycle regulatory network. The intrinsic disorder of AMBRA1 has thus far precluded its structural determination. To solve this problem, we analyzed the dynamics of AMBRA1 using hydrogen deuterium exchange mass spectrometry (HDX-MS). The HDX results indicated that AMBRA1 is a highly flexible protein and can be stabilized upon interaction with DDB1, the adaptor of the Cullin4A/B E3 ligase. Here, we present the cryo-EM structure of AMBRA1 in complex with DDB1 at 3.08 Å resolution. The structure shows that parts of the N- and C-terminal structural regions in AMBRA1 fold together into the highly dynamic WD40 domain and reveals how DDB1 engages with AMBRA1 to create a binding scaffold for substrate recruitment. The N-terminal helix-loop-helix motif and WD40 domain of AMBRA1 associate with the double-propeller fold of DDB1. We also demonstrate that DDB1 binding-defective AMBRA1 mutants prevent ubiquitination of the substrate Cyclin D1 in vitro and increase cell cycle progression. Together, these results provide structural insights into the AMBRA1-ubiquitin ligase complex and suggest a mechanism by which AMBRA1 acts as a hub involved in various physiological processes.
History
DepositionOct 12, 2023-
Header (metadata) releaseDec 20, 2023-
Map releaseDec 20, 2023-
UpdateDec 20, 2023-
Current statusDec 20, 2023Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_37752.png

Downloads & links

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Map

FileDownload / File: emd_37752.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 300 pix.
= 255. Å		0.85 Å/pix.
x 300 pix.
= 255. Å		0.85 Å/pix.
x 300 pix.
= 255. Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.85 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.165
Minimum - Maximum-0.60225266 - 1.2364041
Average (Standard dev.)-0.0012289778 (±0.0361992)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 255.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_37752_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

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Half map: #1

Fileemd_37752_half_map_2.map
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Sample components

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Entire : DDB1-AMBRA1 complex

EntireName: DDB1-AMBRA1 complex
Components
  • Complex: DDB1-AMBRA1 complex
    • Protein or peptide: Activating molecule in BECN1-regulated autophagy protein 1
    • Protein or peptide: DNA damage-binding protein 1

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Supramolecule #1: DDB1-AMBRA1 complex

SupramoleculeName: DDB1-AMBRA1 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Activating molecule in BECN1-regulated autophagy protein 1

MacromoleculeName: Activating molecule in BECN1-regulated autophagy protein 1
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 44.496871 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MKVVPEKNAV RILWGRERGA RAMGAQRLLQ ELVEDKTRWM KWEGKRVELP DSPRSTFLLA FSPDRTLLAS THVNHNIYIT EVKTGKCVH SLIGHRRTPW CVTFHPTISG LIASGCLDGE VRIWDLHGGS ESWFTDSNNA IASLAFHPTA QLLLIATANE I HFWDWSRR ...String:
MKVVPEKNAV RILWGRERGA RAMGAQRLLQ ELVEDKTRWM KWEGKRVELP DSPRSTFLLA FSPDRTLLAS THVNHNIYIT EVKTGKCVH SLIGHRRTPW CVTFHPTISG LIASGCLDGE VRIWDLHGGS ESWFTDSNNA IASLAFHPTA QLLLIATANE I HFWDWSRR EPFAVVKTAS EMERVRLVRF DPLGHYLLTA IVNPSNSNIA NTTYRLQWWD FTKFDLPEIS NASVNVLVQN CK IYNDASC DISADGQLLA AFIPSSQRGF PDEGILAVYS LAPHNLGEML YTKRFGPNAI SVSLSPMGRY VMVGLASRRI LLH PSTEHM VAQVFRLQQA HGGETSMRRV FNVLYPMPAD QRRHVSINSA RWLPEPGLGL AYGTNKGDLV ICRPEALNSG

UniProtKB: Activating molecule in BECN1-regulated autophagy protein 1, Activating molecule in BECN1-regulated autophagy protein 1

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Macromolecule #2: DNA damage-binding protein 1

MacromoleculeName: DNA damage-binding protein 1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 127.097469 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSYNYVVTAQ KPTAVNGCVT GHFTSAEDLN LLIAKNTRLE IYVVTAEGLR PVKEVGMYGK IAVMELFRPK GESKDLLFIL TAKYNACIL EYKQSGESID IITRAHGNVQ DRIGRPSETG IIGIIDPECR MIGLRLYDGL FKVIPLDRDN KELKAFNIRL E ELHVIDVK ...String:
MSYNYVVTAQ KPTAVNGCVT GHFTSAEDLN LLIAKNTRLE IYVVTAEGLR PVKEVGMYGK IAVMELFRPK GESKDLLFIL TAKYNACIL EYKQSGESID IITRAHGNVQ DRIGRPSETG IIGIIDPECR MIGLRLYDGL FKVIPLDRDN KELKAFNIRL E ELHVIDVK FLYGCQAPTI CFVYQDPQGR HVKTYEVSLR EKEFNKGPWK QENVEAEASM VIAVPEPFGG AIIIGQESIT YH NGDKYLA IAPPIIKQST IVCHNRVDPN GSRYLLGDME GRLFMLLLEK EEQMDGTVTL KDLRVELLGE TSIAECLTYL DNG VVFVGS RLGDSQLVKL NVDSNEQGSY VVAMETFTNL GPIVDMCVVD LERQGQGQLV TCSGAFKEGS LRIIRNGIGI HEHA SIDLP GIKGLWPLRS DPNRETDDTL VLSFVGQTRV LMLNGEEVEE TELMGFVDDQ QTFFCGNVAH QQLIQITSAS VRLVS QEPK ALVSEWKEPQ AKNISVASCN SSQVVVAVGR ALYYLQIHPQ ELRQISHTEM EHEVACLDIT PLGDSNGLSP LCAIGL WTD ISARILKLPS FELLHKEMLG GEIIPRSILM TTFESSHYLL CALGDGALFY FGLNIETGLL SDRKKVTLGT QPTVLRT FR SLSTTNVFAC SDRPTVIYSS NHKLVFSNVN LKEVNYMCPL NSDGYPDSLA LANNSTLTIG TIDEIQKLHI RTVPLYES P RKICYQEVSQ CFGVLSSRIE VQDTSGGTTA LRPSASTQAL SSSVSSSKLF SSSTAPHETS FGEEVEVHNL LIIDQHTFE VLHAHQFLQN EYALSLVSCK LGKDPNTYFI VGTAMVYPEE AEPKQGRIVV FQYSDGKLQT VAEKEVKGAV YSMVEFNGKL LASINSTVR LYEWTTEKEL RTECNHYNNI MALYLKTKGD FILVGDLMRS VLLLAYKPME GNFEEIARDF NPNWMSAVEI L DDDNFLGA ENAFNLFVCQ KDSAATTDEE RQHLQEVGLF HLGEFVNVFC HGSLVMQNLG ETSTPTQGSV LFGTVNGMIG LV TSLSESW YNLLLDMQNR LNKVIKSVGK IEHSFWRSFH TERKTEPATG FIDGDLIESF LDISRPKMQE VVANLQYDDG SGM KREATA DDLIKVVEEL TRIH

UniProtKB: DNA damage-binding protein 1

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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: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 58.96 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 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: PDB ENTRY
PDB model - PDB ID:

2b5m

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.08 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 780090
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER

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