Structural Architecture of the CARMA1/Bcl10/MALT1 Signalosome: Nucleation-induced Filamentous Assembly

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2013 Oct 1

PMID 24074955

Citations 90

Authors

Qi Qiao

Chenghua Yang

Chao Zheng

Lorena Fontan

Liron David

Xiong Yu

Clay Bracken

Monica Rosen

Ari Melnick

Edward H Egelman

Hao Wu

Affiliations

Soon will be listed here.

Abstract

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.

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