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- EMDB-45186: Cryo-EM structure of a FAM72A-MKLN1-RANBP9-TWA1 complex -

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Entry
Database: EMDB / ID: EMD-45186
TitleCryo-EM structure of a FAM72A-MKLN1-RANBP9-TWA1 complex
Map data
Sample
  • Complex: Cryo-EM structure a FAM72A-MKLN1-RANBP9-TWA1 subcomplex from focused refinement of CTLH-MKLN1-FAM72A in complex with UNG2
KeywordsE3 ubiquitin ligase / CTLH complex / substrate adapter recruitment / PROTEIN BINDING / LIGASE
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 5.8 Å
AuthorsChana CK / Keszei AFA / Sicheri F
Funding support Canada, 3 items
OrganizationGrant numberCountry
Canadian Institutes of Health Research (CIHR)PJT-178026 Canada
Canadian Institutes of Health Research (CIHR)PJT-180338 Canada
Canadian Institutes of Health Research (CIHR)PJT-186218 Canada
CitationJournal: Nat Commun / Year: 2024
Title: FAM72A degrades UNG2 through the GID/CTLH complex to promote mutagenic repair during antibody maturation.
Authors: Philip Barbulescu / Chetan K Chana / Matthew K Wong / Ines Ben Makhlouf / Jeffrey P Bruce / Yuqing Feng / Alexander F A Keszei / Cassandra Wong / Rukshana Mohamad-Ramshan / Laura C McGary / ...Authors: Philip Barbulescu / Chetan K Chana / Matthew K Wong / Ines Ben Makhlouf / Jeffrey P Bruce / Yuqing Feng / Alexander F A Keszei / Cassandra Wong / Rukshana Mohamad-Ramshan / Laura C McGary / Mohammad A Kashem / Derek F Ceccarelli / Stephen Orlicky / Yifei Fang / Huihui Kuang / Mohammad Mazhab-Jafari / Rossanna C Pezo / Ashok S Bhagwat / Trevor J Pugh / Anne-Claude Gingras / Frank Sicheri / Alberto Martin /
Abstract: A diverse antibody repertoire is essential for humoral immunity. Antibody diversification requires the introduction of deoxyuridine (dU) mutations within immunoglobulin genes to initiate somatic ...A diverse antibody repertoire is essential for humoral immunity. Antibody diversification requires the introduction of deoxyuridine (dU) mutations within immunoglobulin genes to initiate somatic hypermutation (SHM) and class switch recombination (CSR). dUs are normally recognized and excised by the base excision repair (BER) protein uracil-DNA glycosylase 2 (UNG2). However, FAM72A downregulates UNG2 permitting dUs to persist and trigger SHM and CSR. How FAM72A promotes UNG2 degradation is unknown. Here, we show that FAM72A recruits a C-terminal to LisH (CTLH) E3 ligase complex to target UNG2 for proteasomal degradation. Deficiency in CTLH complex components result in elevated UNG2 and reduced SHM and CSR. Cryo-EM structural analysis reveals FAM72A directly binds to MKLN1 within the CTLH complex to recruit and ubiquitinate UNG2. Our study further suggests that FAM72A hijacks the CTLH complex to promote mutagenesis in cancer. These findings show that FAM72A is an E3 ligase substrate adaptor critical for humoral immunity and cancer development.
History
DepositionJun 4, 2024-
Header (metadata) releaseSep 11, 2024-
Map releaseSep 11, 2024-
UpdateSep 11, 2024-
Current statusSep 11, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_45186.png

Downloads & links

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Map

FileDownload / File: emd_45186.map.gz / Format: CCP4 / Size: 103 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.)
0.83 Å/pix.
x 300 pix.
= 247.5 Å		0.83 Å/pix.
x 300 pix.
= 247.5 Å		0.83 Å/pix.
x 300 pix.
= 247.5 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.825 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0057
Minimum - Maximum-0.005087749 - 0.019626355
Average (Standard dev.)0.00015359186 (±0.0011686991)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 247.5 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_45186_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_45186_half_map_2.map
Projections & Slices
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Sample components

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Entire : Cryo-EM structure a FAM72A-MKLN1-RANBP9-TWA1 subcomplex from focu...

EntireName: Cryo-EM structure a FAM72A-MKLN1-RANBP9-TWA1 subcomplex from focused refinement of CTLH-MKLN1-FAM72A in complex with UNG2
Components
  • Complex: Cryo-EM structure a FAM72A-MKLN1-RANBP9-TWA1 subcomplex from focused refinement of CTLH-MKLN1-FAM72A in complex with UNG2

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Supramolecule #1: Cryo-EM structure a FAM72A-MKLN1-RANBP9-TWA1 subcomplex from focu...

SupramoleculeName: Cryo-EM structure a FAM72A-MKLN1-RANBP9-TWA1 subcomplex from focused refinement of CTLH-MKLN1-FAM72A in complex with UNG2
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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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 / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsDetails: This dataset was collected with a 40-degree tilt
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 48.58 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 5.0 µm / Nominal defocus min: -2.4 µm / Nominal magnification: 105000
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 5.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 57296
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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