8CZO

Cryo-EM structure of BCL10 CARD - MALT1 DD filament

Summary for 8CZO

• Entry DOI: 10.2210/pdb8czo/pdb
• EMDB information: 27100
• Descriptor: Mucosa-associated lymphoid tissue lymphoma translocation protein 1, B-cell lymphoma/leukemia 10 (2 entities in total)
• Functional Keywords: filament, cbm complex, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 44
• Total formula weight: 511059.01

Authors

David, L.,Wu, H. (deposition date: 2022-05-25, release date: 2022-06-22, Last modification date: 2024-10-23)

Primary citation

Xia, M.,David, L.,Teater, M.,Gutierrez, J.,Wang, X.,Meydan, C.,Lytle, A.,Slack, G.W.,Scott, D.W.,Morin, R.D.,Onder, O.,Elenitoba-Johnson, K.S.J.,Zamponi, N.,Cerchietti, L.,Lu, T.,Philippar, U.,Fontan, L.,Wu, H.,Melnick, A.M.
BCL10 Mutations Define Distinct Dependencies Guiding Precision Therapy for DLBCL.
Cancer Discov, 12:1922-1941, 2022

PubMed 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 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.

PubMed: 35658124
DOI: 10.1158/2159-8290.CD-21-1566

Experimental method

ELECTRON MICROSCOPY (4.3 Å)