Investigating the novel protein, Ttc7, and its role in transitional B cells (60.2)

Abstract

Abstract Ttc7 is a novel protein of unknown function. Ttc7fsn mutant mice develop an autoimmune phenotype that includes an increase in immature B lymphocytes and marginal zone cells. Here we show that the transitional T1 population is increased two-fold in Ttc7fsn mice and that these cells proliferate upon BCR ligation. Preliminary data also indicate that T1 cells survive BCR stimulation rather than undergo apoptosis. Thus far we've identified two signaling abnormalities in transitional B cells: elevated Erk phosphorylation and decreased CD22 expression. Together, these data suggest that autoreactive transitional B cells are inappropriately activated and allowed to survive rather than undergo clonal deletion or anergy. Results from in silico analyses reveal a number of physical and chemical changes to the Ttc7fsn protein including decreased hydrophobicity, increased polarity and net charge, and the addition of helix-breaking residues. Computational models comparing the TPR domains of Ttc7 and Ttc7fsn show that the mutation disrupts the structure of both the TPR-1 domain and the linking sequence connecting TPR-1 and TPR-2. Further evidence of structural change is provided by preliminary CD spectroscopy, which indicates that the α-helical nature of Ttc7 is altered by the fsn mutation. Based on these findings, we hypothesize that structural changes in the Ttc7fsn protein alter its function and result in faulty molecular and functional regulation of B cell development and function.