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- PDB-8czo: Cryo-EM structure of BCL10 CARD - MALT1 DD filament -

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Basic information

Entry
Database: PDB / ID: 8czo
TitleCryo-EM structure of BCL10 CARD - MALT1 DD filament
Components
  • B-cell lymphoma/leukemia 10
  • Mucosa-associated lymphoid tissue lymphoma translocation protein 1
KeywordsIMMUNE 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 / protein kinase B binding / response to fungus / antifungal innate immune response / CARD domain binding ...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 / protein kinase B binding / response to fungus / antifungal innate immune response / CARD domain binding / positive regulation of mast cell cytokine production / T cell apoptotic process / B cell apoptotic process / negative regulation of mature B cell apoptotic process / programmed cell death / CLEC7A/inflammasome pathway / nuclear export / positive regulation of extrinsic apoptotic signaling pathway / non-canonical NF-kappaB signal transduction / response to food / toll-like receptor signaling pathway / small molecule binding / : / positive regulation of T cell receptor signaling pathway / cytoplasmic microtubule / B cell activation / general transcription initiation factor binding / immunological synapse / NF-kappaB binding / immunoglobulin mediated immune response / cellular defense response / lipopolysaccharide-mediated signaling pathway / positive regulation of phosphorylation / T cell proliferation / positive regulation of interleukin-2 production / positive regulation of interleukin-1 beta production / positive regulation of protein ubiquitination / proteolysis involved in protein catabolic process / neural tube closure / positive regulation of interleukin-8 production / Activation of NF-kappaB in B cells / protein homooligomerization / positive regulation of T cell cytokine production / CLEC7A (Dectin-1) signaling / fibrillar center / defense response / cellular response to mechanical stimulus / 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 / peptidase activity / positive regulation of NF-kappaB transcription factor activity / T cell receptor signaling pathway / protein-macromolecule adaptor activity / cellular response to lipopolysaccharide / protease binding / regulation of apoptotic process / positive regulation of canonical NF-kappaB signal transduction / endopeptidase activity / adaptive immune response / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / transcription coactivator activity / lysosome / 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 / positive regulation of DNA-templated transcription / perinuclear region of cytoplasm / 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 ...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)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 4.3 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 25, 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 1.3Oct 23, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
a: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
b: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
c: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
d: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
e: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
f: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
g: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
h: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
i: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
j: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
k: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
l: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
m: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
n: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
o: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
p: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
q: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
r: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
s: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
t: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
u: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
v: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
A: B-cell lymphoma/leukemia 10
B: B-cell lymphoma/leukemia 10
C: 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
Q: B-cell lymphoma/leukemia 10
R: B-cell lymphoma/leukemia 10
S: B-cell lymphoma/leukemia 10
T: B-cell lymphoma/leukemia 10
U: B-cell lymphoma/leukemia 10
V: B-cell lymphoma/leukemia 10


Theoretical massNumber of molelcules
Total (without water)511,05944
Polymers511,05944
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 ...
Mucosa-associated lymphoid tissue lymphoma translocation protein 1 / MALT lymphoma-associated translocation / Paracaspase


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 ...
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: 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
Has protein modificationY

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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
VitrificationInstrument: FEI VITROBOT MARK III / Cryogen name: ETHANE / Humidity: 100 %

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 47000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm / C2 aperture diameter: 2.7 µm
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 55 e/Å2 / Film or detector model: FEI FALCON II (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 700

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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: 4.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 23000 / Symmetry type: HELICAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00434804
ELECTRON MICROSCOPYf_angle_d0.71246618
ELECTRON MICROSCOPYf_dihedral_angle_d8.114642
ELECTRON MICROSCOPYf_chiral_restr0.0445478
ELECTRON MICROSCOPYf_plane_restr0.0055962

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