Molecular Switches Involving the AP-2 β2 Appendage Regulate Endocytic Cargo Selection and Clathrin Coat Assembly

Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 2XY, United Kingdom.
Developmental Cell (Impact Factor: 10.37). 04/2006; 10(3):329-42. DOI: 10.1016/j.devcel.2006.01.016
Source: PubMed

ABSTRACT Clathrin-associated sorting proteins (CLASPs) expand the repertoire of endocytic cargo sorted into clathrin-coated vesicles beyond the transmembrane proteins that bind physically to the AP-2 adaptor. LDL and GPCRs are internalized by ARH and beta-arrestin, respectively. We show that these two CLASPs bind selectively to the AP-2 beta2 appendage platform via an alpha-helical [DE](n)X(1-2)FXX[FL]XXXR motif, and that this motif also occurs and is functional in the epsins. In beta-arrestin, this motif maintains the endocytosis-incompetent state by binding back on the folded core of the protein in a beta strand conformation. Triggered via a beta-arrestin/GPCR interaction, the motif must be displaced and must undergo a strand to helix transition to enable the beta2 appendage binding that drives GPCR-beta-arrestin complexes into clathrin coats. Another interaction surface on the beta2 appendage sandwich is identified for proteins such as eps15 and clathrin, suggesting a mechanism by which clathrin displaces eps15 to lattice edges during assembly.

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