Fig. 2. Putative domain architecture of the ß-arrestins. By analogy with the known crystal structure of visual arrestin, ß-arrestins are thought to be composed of two major structural domains, N and C, each comprising a seven-stranded ß sandwich. Based upon mutagenesis studies performed using both ß-arrestins and visual arrestin, the ß-arrestins are comprised of two major functional domains, an N-terminal (A) domain responsible for recognition of activated GPCRs and a C-terminal (B) domain responsible for secondary receptor recognition. The A and B domains are separated by a phosphate sensor domain (P). The functionally identified A and B domains correspond approximately to the N and C domains identified crystallographically. N (R1)- and C (R2)-terminal regulatory domains reside at either end of the protein. The R2 domain contains the primary site of ß-arrestin 1 phosphorylation, S412, as well as the LIEF binding motif for clathrin and the RXR binding motif for ß2-adaptin (AP2). The recognition domain for inositol phospholipids (IP6) resides within the B domain. One or more PXXP motifs located within the A domain of ß-arrestin 1 mediates binding to the c-Src-SH3 domain. The MAP kinase, JNK3, and possibly other MAP kinases (MAPKs), interact with ß-arrestin 2 via a consensus MAP kinase recognition sequence, RRSLHL, located within the B domain. Less precisely defined interactions, such as those between ß-arrestin 1 (1-185) and Ask1 and Src-SH1 domains, ß-arrestin 1 and NSF, and ß-arrestin 2 and Mdm2, are also shown. Regions of the protein involved in receptor or membrane recognition are shown in blue, those involved in controlling ß-arrestin interaction with the endocytic machinery are shown in red, while proposed interactions between ß-arrestins and signaling proteins are shown in green.