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- PDB-8czd: Cryo-EM structure of BCL10 R58Q filament -

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Basic information

Entry
Database: PDB / ID: 8czd
TitleCryo-EM structure of BCL10 R58Q filament
ComponentsB-cell lymphoma/leukemia 10
KeywordsIMMUNE SYSTEM / filament / CBM complex
Function / homology
Function and homology information


positive regulation of lymphotoxin A production / polkadots / CBM complex / protein kinase B binding / antifungal innate immune response / CARD domain binding / positive regulation of mast cell cytokine production / T cell apoptotic process / negative regulation of mature B cell apoptotic process / B cell apoptotic process ...positive regulation of lymphotoxin A production / polkadots / CBM complex / protein kinase B binding / antifungal innate immune response / CARD domain binding / positive regulation of mast cell cytokine production / T cell apoptotic process / negative regulation of mature B cell apoptotic process / B cell apoptotic process / programmed cell death / non-canonical NF-kappaB signal transduction / positive regulation of extrinsic apoptotic signaling pathway / response to food / toll-like receptor signaling pathway / positive regulation of T cell receptor signaling pathway / immunoglobulin mediated immune response / immunological synapse / general transcription initiation factor binding / positive regulation of phosphorylation / NF-kappaB binding / cellular defense response / cytoplasmic microtubule / signaling adaptor activity / lipopolysaccharide-mediated signaling pathway / positive regulation of protein ubiquitination / positive regulation of interleukin-8 production / neural tube closure / apoptotic signaling pathway / Activation of NF-kappaB in B cells / cellular response to mechanical stimulus / : / protein homooligomerization / positive regulation of T cell activation / positive regulation of interleukin-6 production / CLEC7A (Dectin-1) signaling / FCERI mediated NF-kB activation / Downstream TCR signaling / T cell receptor signaling pathway / E3 ubiquitin ligases ubiquitinate target proteins / cellular response to lipopolysaccharide / protease binding / protein-macromolecule adaptor activity / adaptive immune response / transcription coactivator activity / lysosome / positive regulation of canonical NF-kappaB signal transduction / positive regulation of apoptotic process / membrane raft / innate immune response / ubiquitin protein ligase binding / positive regulation of DNA-templated transcription / protein-containing complex binding / perinuclear region of cytoplasm / protein-containing complex / nucleoplasm / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
B-cell lymphoma/leukemia 10/E10 / BCL10, CARD domain / CARD domain / CARD caspase recruitment domain profile. / Caspase recruitment domain / Death-like domain superfamily
Similarity search - Domain/homology
B-cell lymphoma/leukemia 10
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 4.6 Å
AuthorsDavid, L. / Wu, H.
Funding support1items
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 24, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 22, 2022Provider: repository / Type: Initial release
Revision 1.1Jun 29, 2022Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Aug 17, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.3Feb 14, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
C: B-cell lymphoma/leukemia 10
Q: B-cell lymphoma/leukemia 10
R: B-cell lymphoma/leukemia 10
S: B-cell lymphoma/leukemia 10
T: B-cell lymphoma/leukemia 10
A: B-cell lymphoma/leukemia 10
B: B-cell lymphoma/leukemia 10
D: B-cell lymphoma/leukemia 10
E: B-cell lymphoma/leukemia 10
F: B-cell lymphoma/leukemia 10
G: B-cell lymphoma/leukemia 10
H: B-cell lymphoma/leukemia 10
I: B-cell lymphoma/leukemia 10
J: B-cell lymphoma/leukemia 10
K: B-cell lymphoma/leukemia 10
L: B-cell lymphoma/leukemia 10
M: B-cell lymphoma/leukemia 10
N: B-cell lymphoma/leukemia 10
O: B-cell lymphoma/leukemia 10
P: B-cell lymphoma/leukemia 10


Theoretical massNumber of molelcules
Total (without water)251,71020
Polymers251,71020
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
B-cell lymphoma/leukemia 10 / B-cell CLL/lymphoma 10 / Bcl-10 / CARD-containing molecule enhancing NF-kappa-B / CARD-like ...B-cell CLL/lymphoma 10 / Bcl-10 / CARD-containing molecule enhancing NF-kappa-B / CARD-like apoptotic protein / hCLAP / CED-3/ICH-1 prodomain homologous E10-like regulator / CIPER / Cellular homolog of vCARMEN / cCARMEN / Cellular-E10 / c-E10 / Mammalian CARD-containing adapter molecule E10 / mE10


Mass: 12585.502 Da / Num. of mol.: 20 / Mutation: R58Q
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

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: helical reconstruction

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Sample preparation

ComponentName: filament / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia phage EcSzw-2 (virus)
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
125 mMtrizma baseTris1
2150 mMSodium ChlorideNaCl1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: C-flat-1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK III / Cryogen name: ETHANE / Humidity: 100 %

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 36000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm / C2 aperture diameter: 2.7 µm
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 38 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 3439

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Processing

SoftwareName: PHENIX / Version: 1.18_3845: / Classification: refinement
EM softwareName: RELION / Version: 3.1 / Category: 3D reconstruction
CTF correctionType: NONE
Helical symmertyAngular rotation/subunit: -100.8 ° / Axial rise/subunit: 5 Å / Axial symmetry: C1
3D reconstructionResolution: 4.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 30000 / Symmetry type: HELICAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00517780
ELECTRON MICROSCOPYf_angle_d0.78923760
ELECTRON MICROSCOPYf_dihedral_angle_d9.4672340
ELECTRON MICROSCOPYf_chiral_restr0.0522760
ELECTRON MICROSCOPYf_plane_restr0.0043040

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