Molecular elucidation of the CBM complex in NF-kappaB activation by antigen recep

Boston Children'S Hospital, Boston MA

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Abstract

DESCRIPTION (provided by applicant): NF-kB signaling has a crucial role in regulating the activation, proliferation and effector functions of lymphocytes in adaptive immune responses. Deregulation of this process results in immunodeficiency, autoimmune diseases, or neoplastic disorders. In the presence of additional co-stimulatory signals, NF-kB is activated by the engagement of TCR with MHC-bound antigen peptides or the interaction of BCR with antigens. The protein kinase C ? (PKC?) of T-cells and PKC¿ of B-cells are recruited to lipid rafts during antigen-receptor triggering and play key roles in TCR- and BCR-induced NF-kB activation, respectively. The ternary complex of CARMA1 [caspase-recruitment domain (CARD) membrane-associated guanylate kinase (MAGUK) protein 1, also known as CARD11], Bcl10 (B-cell lymphoma 10) and MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) acts downstream of PKC? and PKC¿ to induced activation of the IkB kinase (IKK) in both B and T lymphocytes (Figure 1). CARMA1 appears to be constitutively associated with the cytoplasmic membrane. Upon TCR stimulation, CARMA1 is redistributed to the lipid rafts at the immunological synapse to recruit Bcl10 and MALT1 to form the CARMA1-Bcl10-MALT1 (CBM) complex. No structural information is currently available on the CBM complex or its component proteins. In addition, despite having domains that belong to known protein families, CARMA1, Bcl10 and MALT1 exhibit very limited sequence homology to any of the known proteins. To fill this gap, we propose a complete comprehensive structural analysis on the CBM complex, including its assembly mechanisms, conformational changes, enzymatic activities and post-translational modifications. These studies will inevitably provide insights into this important signaling complex.