Assembly mechanism of the CARMA1-BCL10-MALT1-TRAF6 signalosome.
Proc Natl Acad Sci U S A
; 115(7): 1499-1504, 2018 02 13.
Article
em En
| MEDLINE
| ID: mdl-29382759
ABSTRACT
The CARMA1-BCL10-MALT1 (CBM) signalosome is a central mediator of T cell receptor and B cell receptor-induced NF-κB signaling that regulates multiple lymphocyte functions. While caspase-recruitment domain (CARD) membrane-associated guanylate kinase (MAGUK) protein 1 (CARMA1) nucleates B cell lymphoma 10 (BCL10) filament formation through interactions between CARDs, mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a paracaspase with structural similarity to caspases, which recruits TNF receptor-associated factor 6 (TRAF6) for K63-linked polyubiquitination. Here we present cryo-electron microscopy (cryo-EM) structure of the BCL10 CARD filament at 4.0-Å resolution. The structure redefines CARD-CARD interactions compared with the previous EM structure determined from a negatively stained sample. Surprisingly, time-lapse confocal imaging shows that BCL10 polymerizes in a unidirectional manner. CARMA1, the BCL10 nucleator, serves as a hub for formation of star-shaped filamentous networks of BCL10 and significantly decreases the lag period of BCL10 polymerization. Cooperative MALT1 interaction with BCL10 filaments observed under EM suggests immediate dimerization of MALT1 in the BCL10 filamentous scaffold. In addition, TRAF6 cooperatively decorates CBM filaments to form higher-order assemblies, likely resulting in all-or-none activation of the downstream pathway. Collectively, these data reveal biophysical mechanisms in the assembly of the CARMA1-BCL10-MALT1-TRAF6 complex for signal transduction.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fator 6 Associado a Receptor de TNF
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Proteínas Adaptadoras de Sinalização CARD
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Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa
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Proteína 10 de Linfoma CCL de Células B
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Guanilato Ciclase
Limite:
Humans
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Ano de publicação:
2018
Tipo de documento:
Article