+Open data
-Basic information
Entry | Database: PDB / ID: 8czo | ||||||
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Title | Cryo-EM structure of BCL10 CARD - MALT1 DD filament | ||||||
Components |
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Keywords | IMMUNE SYSTEM / filament / CBM complex | ||||||
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 / CBM complex / regulation of T cell receptor signaling pathway / 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 / CBM complex / regulation of T cell receptor signaling pathway / 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 / CLEC7A/inflammasome pathway / positive regulation of extrinsic apoptotic signaling pathway / nuclear export / response to food / non-canonical NF-kappaB signal transduction / toll-like receptor signaling pathway / B cell activation / positive regulation of T cell receptor signaling pathway / cytoplasmic microtubule / positive regulation of cysteine-type endopeptidase activity involved in apoptotic process / small molecule binding / positive regulation of phosphorylation / general transcription initiation factor binding / immunological synapse / NF-kappaB binding / immunoglobulin mediated immune response / cellular defense response / T cell proliferation / lipopolysaccharide-mediated signaling pathway / positive regulation of interleukin-2 production / proteolysis involved in protein catabolic process / positive regulation of interleukin-1 beta production / positive regulation of protein ubiquitination / neural tube closure / positive regulation of interleukin-8 production / Activation of NF-kappaB in B cells / cellular response to mechanical stimulus / protein homooligomerization / positive regulation of T cell cytokine production / CLEC7A (Dectin-1) signaling / fibrillar center / defense response / FCERI mediated NF-kB activation / positive regulation of interleukin-6 production / 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 / protein-macromolecule adaptor activity / T cell receptor signaling pathway / positive regulation of canonical NF-kappaB signal transduction / endopeptidase activity / protease binding / cellular response to lipopolysaccharide / regulation of apoptotic process / transcription coactivator activity / adaptive immune response / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / lysosome / membrane raft / positive regulation of apoptotic process / cysteine-type endopeptidase activity / innate immune response / ubiquitin protein ligase binding / positive regulation of DNA-templated transcription / negative regulation of apoptotic process / protein-containing complex binding / perinuclear region of cytoplasm / protein-containing complex / proteolysis / identical protein binding / nucleus / cytoplasm / cytosol Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 4.3 Å | ||||||
Authors | David, L. / Wu, H. | ||||||
Funding support | 1items
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Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8czo.cif.gz | 716.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8czo.ent.gz | 613.8 KB | Display | PDB format |
PDBx/mmJSON format | 8czo.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8czo_validation.pdf.gz | 1.2 MB | Display | wwPDB validaton report |
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Full document | 8czo_full_validation.pdf.gz | 1.2 MB | Display | |
Data in XML | 8czo_validation.xml.gz | 81.9 KB | Display | |
Data in CIF | 8czo_validation.cif.gz | 133.5 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/cz/8czo ftp://data.pdbj.org/pub/pdb/validation_reports/cz/8czo | HTTPS FTP |
-Related structure data
Related structure data | 27100MC 8czdC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | Mass: 10615.389 Da / Num. of mol.: 22 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: MALT1, MLT / Production host: Escherichia phage EcSzw-2 (virus) References: UniProt: Q9UDY8, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases #2: Protein | Mass: 12614.566 Da / Num. of mol.: 22 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: BCL10, CIPER, CLAP / Production host: Escherichia phage EcSzw-2 (virus) / References: UniProt: O95999 |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: FILAMENT / 3D reconstruction method: helical reconstruction |
-Sample preparation
Component | Name: filament / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT | |||||||||||||||
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Molecular weight | Experimental value: NO | |||||||||||||||
Source (natural) | Organism: Homo sapiens (human) | |||||||||||||||
Source (recombinant) | Organism: Escherichia phage EcSzw-2 (virus) | |||||||||||||||
Buffer solution | pH: 7.5 | |||||||||||||||
Buffer component |
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Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | |||||||||||||||
Vitrification | Instrument: FEI VITROBOT MARK III / Cryogen name: ETHANE / Humidity: 100 % |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal magnification: 47000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm / C2 aperture diameter: 2.7 µm |
Specimen holder | Cryogen: NITROGEN |
Image recording | Electron dose: 55 e/Å2 / Film or detector model: FEI FALCON II (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 700 |
-Processing
Software | Name: PHENIX / Version: 1.18_3845: / Classification: refinement | ||||||||||||||||||||||||
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EM software | Name: RELION / Version: 3.1 / Category: 3D reconstruction | ||||||||||||||||||||||||
CTF correction | Type: NONE | ||||||||||||||||||||||||
Helical symmerty | Angular rotation/subunit: -100.8 ° / Axial rise/subunit: 5 Å / Axial symmetry: C1 | ||||||||||||||||||||||||
3D reconstruction | Resolution: 4.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 23000 / Symmetry type: HELICAL | ||||||||||||||||||||||||
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