TitleStructural architecture of the CARMA1/Bcl10/MALT1 signalosome: nucleation-induced filamentous assembly.
Publication TypeJournal Article
Year of Publication2013
AuthorsQiao, Qi, Yang Chenghua, Zheng Chao, Fontan Lorena, David Liron, Yu Xiong, Bracken Clay, Rosen Monica, Melnick Ari, Egelman Edward H., and Wu Hao
JournalMol Cell
Date Published2013 Sep 26
KeywordsAdaptor Proteins, Signal Transducing, B-Cell CLL-Lymphoma 10 Protein, Binding Sites, CARD Signaling Adaptor Proteins, Caspases, Crystallography, X-Ray, Gene Expression Regulation, Guanylate Cyclase, Humans, Jurkat Cells, Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein, Multiprotein Complexes, Neoplasm Proteins, NF-kappa B, Protein Binding, Protein Structure, Secondary, Signal Transduction

<p>The CARMA1/Bcl10/MALT1 (CBM) signalosome mediates antigen receptor-induced NF-κB signaling to regulate multiple lymphocyte functions. While CARMA1 and Bcl10 contain caspase recruitment domains (CARDs), MALT1 is a paracaspase with structural similarity to caspases. Here we show that the reconstituted CBM signalosome is a helical filamentous assembly in which substoichiometric CARMA1 nucleates Bcl10 filaments. Bcl10 filament formation is a highly cooperative process whose threshold is sensitized by oligomerized CARMA1 upon receptor activation. In cells, both cotransfected CARMA1/Bcl10 complex and the endogenous CBM signalosome are filamentous morphologically. Combining crystallography, nuclear magnetic resonance, and electron microscopy, we reveal the structure of the Bcl10 CARD filament and the mode of interaction between CARMA1 and Bcl10. Structure-guided mutagenesis confirmed the observed interfaces in Bcl10 filament assembly and MALT1 activation in vitro and NF-κB activation in cells. These data support a paradigm of nucleation-induced signal transduction with threshold response due to cooperativity and signal amplification by polymerization.</p>

Alternate JournalMol Cell
PubMed ID24074955
PubMed Central IDPMC3929958
Grant ListR01EB001567 / EB / NIBIB NIH HHS / United States
R01 AI089882 / AI / NIAID NIH HHS / United States
R01AI089882 / AI / NIAID NIH HHS / United States
R01 EB001567 / EB / NIBIB NIH HHS / United States
R01 AI045937 / AI / NIAID NIH HHS / United States