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Structures of autoinhibited and polymerized forms of CARD9 reveal mechanisms of CARD9 and CARD11 activation
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Structures of autoinhibited and polymerized forms of CARD9 reveal mechanisms of CARD9 and CARD11 activation
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Journal Article
Structures of autoinhibited and polymerized forms of CARD9 reveal mechanisms of CARD9 and CARD11 activation
2019
Overview
CARD9 and CARD11 drive immune cell activation by nucleating Bcl10 polymerization, but are held in an autoinhibited state prior to stimulation. Here, we elucidate the structural basis for this autoinhibition by determining the structure of a region of CARD9 that includes an extensive interface between its caspase recruitment domain (CARD) and coiled-coil domain. We demonstrate, for both CARD9 and CARD11, that disruption of this interface leads to hyperactivation in cells and to the formation of Bcl10-templating filaments in vitro, illuminating the mechanism of action of numerous oncogenic mutations of CARD11. These structural insights enable us to characterize two similar, yet distinct, mechanisms by which autoinhibition is relieved in the course of canonical CARD9 or CARD11 activation. We also dissect the molecular determinants of helical template assembly by solving the structure of the CARD9 filament. Taken together, these findings delineate the structural mechanisms of inhibition and activation within this protein family.
CARD9 and CARD11 propagate signaling by nucleating Bcl10 polymerization in immune cells and are both held in an autoinhibited state prior to activation. Here, the authors combine structural, biochemical, and cell-based approaches to reveal the structural basis for CARD9/11 autoinhibition and show that the two proteins are activated through similar but distinct mechanisms.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 101/58
/ 101/6
/ B-Cell CLL-Lymphoma 10 Protein - metabolism
/ CARD Signaling Adaptor Proteins - genetics
/ CARD Signaling Adaptor Proteins - immunology
/ CARD Signaling Adaptor Proteins - metabolism
/ CARD Signaling Adaptor Proteins - ultrastructure
/ Caspase
/ Coils
/ Guanylate Cyclase - genetics
/ Guanylate Cyclase - immunology
/ Guanylate Cyclase - metabolism
/ Guanylate Cyclase - ultrastructure
/ Humanities and Social Sciences
/ Humans
/ Kinases
/ Lymphoma
/ Mutation
/ Nuclear Magnetic Resonance, Biomolecular
/ Protein Conformation, alpha-Helical
/ Protein Multimerization - immunology
/ Proteins
/ Recombinant Proteins - genetics
/ Recombinant Proteins - immunology
/ Recombinant Proteins - metabolism
/ Recombinant Proteins - ultrastructure
/ Science
