Structural and functional studies of sTALL-1

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TALL-1 was recently identified as a member of the tumor necrosis factor (TNF) ligand family, which stimulates B cell proliferation, and the secretion of immunoglobulins. Overexpression of TALL-1 in mice lead to autoimmune-like manifestations such as increased number of mature B cells, high levels of rheumatoid factors, circulating immune complexes, anti- DNA autoantibodies, and Ig deposition in the kidney. Two receptors for the TALL-1 have been identified, which are BCMA and TACI. BCMA, an orphan receptor of the TNF receptor family (TNFR), is specifically expressed by B cells or B cell derived cells and contains only one cysteine rich motif contrasting three to four motifs in other family members. The structure of the functional soluble portion of TALL-1 (sTALL-1) has been determined at 3.0 Angstrom units. sTALL-1 forms a virus-like structure through novel trimer-trimer interactions. This virus- like structure also exists in solution. We speculate that this novel structure could be the functional unit for TALL-1 in vivo. Finally, signal transduction from outside the cell membrane to inside the cell membrane by TNF/TNFR is not clearly understood. The goal of this proposal is to elucidate the unique regulation mechanisms of TALL-1 and TALL-1 receptors and universal mechanisms for the whole TNF/TNFR super family members through x- ray crystallography. Other approaches such as electron microscopy, single molecule tracking 3-D microscopy rebuilding techniques, mutagenisis, dynamic light scattering, and ultracentrifugation will also be used. Three specific aims are proposed. Aim 1: Structural and functional characterization of sTALL-1. Aim 2: Determining the structural basis of sTALL-1 interaction with extra cellular domains of BCMA and TACI. Aim 3: Characterizing the signal transduction mechanisms of TALL-1 BCMA or TACI through the cell membrane. All information derived from the above goal can be used to identify molecular targets for drug development against autoimmune diseases and cancer induced by TALL-1 or other TNF family member malfunctioning.