Molecular architecture and regulation of BCL10-MALT1 filaments

• Published in: Nature communications Vol. 9; no. 1; pp. 4041 - 12
• Main Authors: Schlauderer, Florian, Seeholzer, Thomas, Desfosses, Ambroise, Gehring, Torben, Strauss, Mike, Hopfner, Karl-Peter, Gutsche, Irina, Krappmann, Daniel, Lammens, Katja
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.10.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 101/28; 13; 13/95; 631/250/516/1909; 631/45/535/1258/1259; Adaptive immunity; Architecture; Assembly; B-Cell CLL-Lymphoma 10 Protein - chemistry; B-Cell CLL-Lymphoma 10 Protein - metabolism; B-Cell CLL-Lymphoma 10 Protein - ultrastructure; Bcl-10 protein; Biochemistry, Molecular Biology; CARD Signaling Adaptor Proteins - metabolism; Caspase; CD4 antigen; Cryoelectron Microscopy; Domains; Filaments; Guanylate Cyclase - metabolism; Humanities and Social Sciences; Immune response; Immune system; Immunoglobulins; Interfaces; Kinases; Life Sciences; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Lymphoma; Models, Chemical; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein - chemistry; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein - metabolism; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein - ultrastructure; multidisciplinary; Mutagenesis; Mutation; NF-κB protein; Paracaspases; Protein Conformation; Proteins; Science; Science (multidisciplinary); Signaling; Structural Biology; Substrates
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-06573-8

The CARD11-BCL10-MALT1 (CBM) complex triggers the adaptive immune response in lymphocytes and lymphoma cells. CARD11/CARMA1 acts as a molecular seed inducing BCL10 filaments, but the integration of MALT1 and the assembly of a functional CBM complex has remained elusive. Using cryo-EM we solved the helical structure of the BCL10-MALT1 filament. The structural model of the filament core solved at 4.9 Å resolution identified the interface between the N-terminal MALT1 DD and the BCL10 caspase recruitment domain. The C-terminal MALT1 Ig and paracaspase domains protrude from this core to orchestrate binding of mediators and substrates at the filament periphery. Mutagenesis studies support the importance of the identified BCL10-MALT1 interface for CBM complex assembly, MALT1 protease activation and NF-κB signaling in Jurkat and primary CD4 T-cells. Collectively, we present a model for the assembly and architecture of the CBM signaling complex and how it functions as a signaling hub in T-lymphocytes. The BCL10-MALT1 complex is a central signaling hub in lymphocytes and linked to various human immune pathologies. Here the authors present the cryo-EM structure of the BCL10-MALT1 filament core and verify the identified BCL10/MALT1 interface with mutagenesis studies.