SEQUENCE AND 3D STRUCTURAL RELATIONSHIPS BETWEEN MAMMALIAN RAS-SPECIFIC AND RHO-SPECIFIC GTPASE-ACTIVATING PROTEINS (GAPS) - THE CRADLE FOLD

An extensive study of both sequence and recent 3D structural data conc erning GTPase interacting domains of Ras- and Rho-specific GTPase-acti vating proteins (GAPs) shows that these two subfamilies share a same 3 D scaffold and are thus related to each other. This relationship has h eretofore remained undetected although these domains of similar size a re both totally alpha-helical and activate nearly structurally identic al targets (Ras and Rho proteins). In this report, sequence similariti es correlated to 3D structures of p120rasGAP and p50rhoGAP were detect ed using the sensitive two-dimensional method hydrophobic cluster anal ysis (HCA), These patterns were further extended to other members in e ach subfamily and the geometry orientation of crucial arginines R789 i n p120 and R282 in p50 and of important stabilizing residues like p120 R903 and p50N391 was confirmed, This overall structural relationship i s centered on an invariant motif of three consecutive helices that we suggest to name the 'cradle fold?. This observation opens new perspect ives to understand how small GTPases are specifically regulated. (C) 1 998 Federation of European Biochemical Societies.