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- EMDB-27100: Cryo-EM structure of BCL10 CARD - MALT1 DD filament -

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Basic information

Entry
Database: EMDB / ID: EMD-27100
TitleCryo-EM structure of BCL10 CARD - MALT1 DD filament
Map dataCryoEM structure BCL10 CARD-MALT1
Sample
  • Complex: filament
    • Protein or peptide: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
    • Protein or peptide: B-cell lymphoma/leukemia 10
Function / homology
Function and homology information


positive regulation of lymphotoxin A production / polkadots / B-1 B cell differentiation / positive regulation of T-helper 17 cell differentiation / regulation of T cell receptor signaling pathway / CBM complex / antifungal innate immune response / protein kinase B binding / response to fungus / T cell apoptotic process ...positive regulation of lymphotoxin A production / polkadots / B-1 B cell differentiation / positive regulation of T-helper 17 cell differentiation / regulation of T cell receptor signaling pathway / CBM complex / antifungal innate immune response / protein kinase B binding / response to fungus / T cell apoptotic process / positive regulation of mast cell cytokine production / CARD domain binding / programmed cell death / negative regulation of mature B cell apoptotic process / B cell apoptotic process / activation of NF-kappaB-inducing kinase activity / CLEC7A/inflammasome pathway / nuclear export / positive regulation of extrinsic apoptotic signaling pathway / response to food / toll-like receptor signaling pathway / B cell activation / positive regulation of T cell receptor signaling pathway / non-canonical NF-kappaB signal transduction / small molecule binding / positive regulation of cysteine-type endopeptidase activity involved in apoptotic process / immunoglobulin mediated immune response / immunological synapse / general transcription initiation factor binding / NF-kappaB binding / canonical NF-kappaB signal transduction / cellular defense response / cytoplasmic microtubule / T cell proliferation / positive regulation of phosphorylation / lipopolysaccharide-mediated signaling pathway / positive regulation of interleukin-2 production / proteolysis involved in protein catabolic process / positive regulation of protein ubiquitination / positive regulation of interleukin-1 beta production / neural tube closure / positive regulation of interleukin-8 production / Activation of NF-kappaB in B cells / protein homooligomerization / defense response / fibrillar center / CLEC7A (Dectin-1) signaling / positive regulation of T cell cytokine production / FCERI mediated NF-kB activation / positive regulation of interleukin-6 production / cellular response to mechanical stimulus / ubiquitin-protein transferase activity / : / positive regulation of T cell activation / Downstream TCR signaling / E3 ubiquitin ligases ubiquitinate target proteins / positive regulation of NF-kappaB transcription factor activity / peptidase activity / T cell receptor signaling pathway / regulation of apoptotic process / positive regulation of canonical NF-kappaB signal transduction / endopeptidase activity / cellular response to lipopolysaccharide / protease binding / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / adaptive immune response / lysosome / transcription coactivator activity / positive regulation of apoptotic process / membrane raft / cysteine-type endopeptidase activity / innate immune response / ubiquitin protein ligase binding / protein-containing complex binding / negative regulation of apoptotic process / perinuclear region of cytoplasm / positive regulation of DNA-templated transcription / protein-containing complex / proteolysis / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
B-cell lymphoma/leukemia 10/E10 / BCL10, CARD domain / Mucosa-associated lymphoid tissue lymphoma translocation protein 1 / MALT1, death domain / MALT1 immunoglobulin-like domain / MALT1 Ig-like domain / CARD domain / CARD caspase recruitment domain profile. / Caspase recruitment domain / Immunoglobulin domain ...B-cell lymphoma/leukemia 10/E10 / BCL10, CARD domain / Mucosa-associated lymphoid tissue lymphoma translocation protein 1 / MALT1, death domain / MALT1 immunoglobulin-like domain / MALT1 Ig-like domain / CARD domain / CARD caspase recruitment domain profile. / Caspase recruitment domain / Immunoglobulin domain / Peptidase C14, p20 domain / Caspase family p20 domain profile. / : / Caspase domain / Caspase-like domain superfamily / Immunoglobulin domain / Death-like domain superfamily / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Immunoglobulin subtype / Immunoglobulin / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
B-cell lymphoma/leukemia 10 / Mucosa-associated lymphoid tissue lymphoma translocation protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 4.3 Å
AuthorsDavid L / Wu H
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Cancer Discov / Year: 2022
Title: BCL10 Mutations Define Distinct Dependencies Guiding Precision Therapy for DLBCL.
Authors: Min Xia / Liron David / Matt Teater / Johana Gutierrez / Xiang Wang / Cem Meydan / Andrew Lytle / Graham W Slack / David W Scott / Ryan D Morin / Ozlem Onder / Kojo S J Elenitoba-Johnson / ...Authors: Min Xia / Liron David / Matt Teater / Johana Gutierrez / Xiang Wang / Cem Meydan / Andrew Lytle / Graham W Slack / David W Scott / Ryan D Morin / Ozlem Onder / Kojo S J Elenitoba-Johnson / Nahuel Zamponi / Leandro Cerchietti / Tianbao Lu / Ulrike Philippar / Lorena Fontan / Hao Wu / Ari M Melnick /
Abstract: Activated B cell-like diffuse large B-cell lymphomas (ABC-DLBCL) have unfavorable outcomes and chronic activation of CARD11-BCL10-MALT1 (CBM) signal amplification complexes that form due to ...Activated B cell-like diffuse large B-cell lymphomas (ABC-DLBCL) have unfavorable outcomes and chronic activation of CARD11-BCL10-MALT1 (CBM) signal amplification complexes that form due to polymerization of BCL10 subunits, which is affected by recurrent somatic mutations in ABC-DLBCLs. Herein, we show that BCL10 mutants fall into at least two functionally distinct classes: missense mutations of the BCL10 CARD domain and truncation of its C-terminal tail. Truncating mutations abrogated a motif through which MALT1 inhibits BCL10 polymerization, trapping MALT1 in its activated filament-bound state. CARD missense mutations enhanced BCL10 filament formation, forming glutamine network structures that stabilize BCL10 filaments. Mutant forms of BCL10 were less dependent on upstream CARD11 activation and thus manifested resistance to BTK inhibitors, whereas BCL10 truncating but not CARD mutants were hypersensitive to MALT1 inhibitors. Therefore, BCL10 mutations are potential biomarkers for BTK inhibitor resistance in ABC-DLBCL, and further precision can be achieved by selecting therapy based on specific biochemical effects of distinct mutation classes.
SIGNIFICANCE: ABC-DLBCLs feature frequent mutations of signaling mediators that converge on the CBM complex. We use structure-function approaches to reveal that BCL10 mutations fall into two distinct ...SIGNIFICANCE: ABC-DLBCLs feature frequent mutations of signaling mediators that converge on the CBM complex. We use structure-function approaches to reveal that BCL10 mutations fall into two distinct biochemical classes. Both classes confer resistance to BTK inhibitors, whereas BCL10 truncations confer hyperresponsiveness to MALT1 inhibitors, providing a road map for precision therapies in ABC-DLBCLs. See related commentary by Phelan and Oellerich, p. 1844. This article is highlighted in the In This Issue feature, p. 1825.
History
DepositionMay 25, 2022-
Header (metadata) releaseJun 22, 2022-
Map releaseJun 22, 2022-
UpdateAug 17, 2022-
Current statusAug 17, 2022Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_27100.png

Downloads & links

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Map

FileDownload / File: emd_27100.map.gz / Format: CCP4 / Size: 137.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryoEM structure BCL10 CARD-MALT1
Voxel sizeX=Y=Z: 1.1019 Å
Density
Contour LevelBy AUTHOR: 0.04
Minimum - Maximum-0.017832788 - 1.995209
Average (Standard dev.)0.005064691 (±0.050215486)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions330330330
Spacing330330330
CellA=B=C: 363.62698 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: half2 map

Fileemd_27100_half_map_1.map
Annotationhalf2 map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half1 map

Fileemd_27100_half_map_2.map
Annotationhalf1 map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : filament

EntireName: filament
Components
  • Complex: filament
    • Protein or peptide: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
    • Protein or peptide: B-cell lymphoma/leukemia 10

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Supramolecule #1: filament

SupramoleculeName: filament / type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Escherichia phage EcSzw-2 (virus)

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Macromolecule #1: Mucosa-associated lymphoid tissue lymphoma translocation protein 1

MacromoleculeName: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
type: protein_or_peptide / ID: 1 / Number of copies: 22 / Enantiomer: LEVO
EC number: Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 10.615389 KDa
Recombinant expressionOrganism: Escherichia phage EcSzw-2 (virus)
SequenceString:
TLNRLREPLL RRLSELLDQA PEGRGWRRLA ELAGSRGRLR LSCLDLEQCS LKVLEPEGSP SLCLLKLMGE KGCTVTELSD FLQAMEHTE VLQLL

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Macromolecule #2: B-cell lymphoma/leukemia 10

MacromoleculeName: B-cell lymphoma/leukemia 10 / type: protein_or_peptide / ID: 2 / Number of copies: 22 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 12.614566 KDa
Recombinant expressionOrganism: Escherichia phage EcSzw-2 (virus)
SequenceString:
EEDLTEVKKD ALENLRVYLC EKIIAERHFD HLRAKKILSR EDTEEISCRT SSRKRAGKLL DYLQENPKGL DTLVESIRRE KTQNFLIQK ITDEVLKLRN IKLEHLK

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

BufferpH: 7.5
Component:
ConcentrationFormulaName
25.0 mMTristrizma base
150.0 mMNaClSodium chlorideSodium Chloride
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Instrument: FEI VITROBOT MARK III

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 2.7 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 47000
Sample stageCooling holder cryogen: NITROGEN
Image recordingFilm or detector model: FEI FALCON II (4k x 4k) / Number grids imaged: 1 / Number real images: 700 / Average electron dose: 55.0 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:

7314

Final angle assignmentType: NOT APPLICABLE
Final reconstructionApplied symmetry - Helical parameters - Δz: 5.0 Å
Applied symmetry - Helical parameters - Δ&Phi: -100.8 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 4.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1) / Number images used: 23000

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