Insights into SCF ubiquitin ligases from the structure of the Skp1-Skp2 complex

F-box proteins are members of a large family that regulates the cell cycle, the immune response, signalling cascades and developmental programmes by t argeting proteins, such as cyclins, cyclin-dependent kinase inhibitors, I k appaB alpha and beta -catenin, for ubiquitination (reviewed in refs 1-3). F -box proteins are the substrate-recognition components of SCF (Skp1-Cullin- F-box protein) ubiquitin-protein ligases(4,5). They bind the SCF constant c atalytic core by means of the F-box motif interacting with Skp1, and they b ind substrates through their variable protein-protein interaction domains(6 ). The large number of F-box proteins is thought to allow ubiquitination of numerous, diverse substrates(6). Most organisms have several Skp1 family m embers, but the function of these Skp1 homologues and the rules of recognit ion between different F-box and Skp1 proteins remain unknown. Here we descr ibe the crystal structure of the human F-box protein Skp2 bound to Skp1. Sk p1 recruits the F-box protein through a bipartite interface involving both the F-box and the substrate-recognition domain. The structure raises the po ssibility that different Skp1 family members evolved to function with diffe rent subsets of F-box proteins, and suggests that the F-box protein may not only recruit substrate, but may also position it optimally for the ubiquit ination reaction.