Molecular Cell
Volume 51, Issue 6, 26 September 2013, Pages 766-779
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Article
Structural Architecture of the CARMA1/Bcl10/MALT1 Signalosome: Nucleation-Induced Filamentous Assembly

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Highlights

  • CARMA1 nucleates Bcl10 filaments in the CBM signalosome

  • The EM structure reveals mode of interactions in the CARMA1/Bcl10 complex

  • The interactions are validated by mutagenesis in vitro and in cells

  • The filamentous CBM complex implicates mechanism of signal amplification

Summary

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.

Cited by (0)

7

These authors contributed equally to this work

8

Present address: Department of Molecular Pharmacology and Chemistry, Sloan-Kettering Institute, New York, NY 10021, USA

9

Present address: Pfizer Inc., 445 Eastern Point Road, Groton, CT 06340, USA