Structural Basis for TSC-1 TSC-2 Complex Formation

Tuberous sclerosis complex TSC is a neurological disorder characterized by the formation of hamartomas in brain skin kidney and other organs. The tumor suppressor genes TSCI and TSC2 encode the proteins hamartin and tuberin respectively. The tuberin1-418 region interacts with hamartin302-430 forming the TSC1-TSC2 complex that functions in cell growth regulation. Certain mutations in TSC patients disrupt the hamartin-tuberin interaction indicating that association of these proteins is required for their growth suppressing function. However the mechanisms underlying their interaction are poorly understood because their three-dimensional structures are not known. To obtain structural insights into the hamartin-tuberin interaction the hamartin302-430 and tuberin11-418 domains were expressed in Escherichia coli cells and purified to homogeneity. Attempts to crystallize the isolated hamartin302-430 and tuberin11-418 domains yielded small crystals whereas the hamartin-tuberin heterodimer did not produce crystals. Experiments are in progress to produce diffraction quality crystals of these proteins and determine their structures.