The 'intelligent adaptor' Dab2 regulates clathrin-mediated endocytosi

Clathrin-mediated endocytosis (CME) is an essential process by which cells internalize plasma membrane proteins. The master regulator of the process is thought to be the adaptor protein AP2, which organizes receptors, clathrin, and other necessary factors at the plasma membrane. Disabled-2 (Dab2) is an adaptor protein that allows AP2 to internalize receptors to which it cannot directly bind, such as the low-density lipoprotein receptor (LDLR) and integrin beta1. Dab2 has been shown to function independently of AP2 under some conditions. I hypothesized that this AP2-independent function of Dab2 might require Dab2 to interact directly with various endocytic accessory proteins normally recruited by AP2. Here I report the direct interaction of Dab2 with three endocytic accessory proteins, the F-BAR protein FCHO2 and the EH domain proteins Eps15 and Intersectin (ITSN). Interestingly, FCHO2 and the EH domain proteins are both important for the organization and structure of clathrin-coated pits (CCPs). FCHO2 and EH domain proteins are required for CME and their interaction with Dab2 is required for Dab2-mediated endocytosis. The mere presence of EH domain proteins in CCPs is not sufficient for internalization of Dab2 cargoes; Eps15 and ITSN must directly bind to Dab2 to permit receptor endocytosis. This suggests that a cargo-adaptor-EH domain protein complex is required for CME. I also give evidence that Dab2 exists in both "open" and "closed" states and that the change between the two may be regulated by cargo binding. While common perception holds that adaptor proteins simply link two incompatible proteins together, I propose that Dab2 is an "intelligent adaptor" which senses the presence of one molecule and undergoes a conformational change to permit the binding of others.