Fig. 3. Inositide and peptide recognition by adaptor proteins. (A) The trunk domain of the tetrameric clathrin adaptor AP-2 binds phosphoinositides in two locations. One of the binding sites is at a peripheral position in the N-terminus of the 2 subunit (green). The other site (red circle labeled 1) is within the µ2 subunit (brown). Binding of the lipid to this site is believed to be one of the factors inducing a conformational change that allows binding of the internalization motif Yxx to µ2 at a site that is otherwise blocked by interaction with the ß2 subunit (gray circle labeled 2). (B) The binding of Ins(1,4,5)P₃ [mimicking PtdIns(4,5)P₂] to CALM occurs at a helical domain (green) in a similarly peripheral position to that seen in AP-2. By contrast, in the ENTH domain of epsin, an additional helix (helix 0), which is disordered in the structure without the inositide, contributes to the coordination of the lipid headgroup within the multi-helical structure that is otherwise very similar to CALM/ANTH domains. (C) The structure of ß-arrestin-1 resembles that of the C-terminal multi-stranded domain of the AP-2 µ2 subunit. The electropositive groove that interacts with phosphorylated tails of G protein-coupled receptors (gray circle labeled 2) and the adjacent inositide-binding pocket (red circle labeled 1) are very reminiscent of the peptide- and lipid-binding sites of the AP-2 µ2 domain. Gray arrows indicate clathrin- and ß2-adaptin-binding sites. The PDB accession numbers used are: 1GW5, AP-2 core (Collins et al., 2002); 1HES, µ2-C-terminal (Owen and Evans, 1998); 1H0A, Epsin-ENTH (Ford et al., 2002); 1HG2, CALM-ANTH (Ford et al., 2001).