Implication of tubby proteins as transcription factors by structure-based functional analysis

Tubby-like proteins (TULPs) are found in a broad range of multicellular org anisms. In mammals, genetic mutation of tubby or other TULPs can result in one dr more of three disease phenotypes: obesity (from which the name "tubb y" is derived), retinal degeneration, and hearing loss. These disease pheno types indicate a vital role for tubby proteins; however, no biochemical fun ction has yet been ascribed to any member of this protein family. A structu re-directed approach was employed to investigate the biological function of these proteins. The crystal structure of the core domain from mouse tubby was determined at a resolution of 1.9 angstroms. From primarily structural clues, experiments were devised, the results of which suggest that TULPs ar e a unique family of bipartite transcription factors.