Adaptor protein complex 2 dileucine motif binding site (AP2 dileucine site)

The Adaptor protein complex 2 (AP2) dileucine motif binding site is a specialized protein-protein interaction pocket located at the interface of the alpha and sigma-2 subunits of the heterotetrameric AP2 complex (Kelly et al., 2008, Nature). Its primary biological function is to recognize and bind [DE]XXXL[LI]-type dileucine-based sorting signals found in the cytosolic tails of transmembrane cargo proteins, facilitating their incorporation into clathrin-coated vesicles for endocytosis (Traub, 2009, Annu. Rev. Biochem.). This site is a critical node in clathrin-mediated endocytosis, regulating the internalisation of various receptors and transporters essential for cellular homeostasis. In the context of disease, the site is famously hijacked by the HIV-1 Nef protein, which acts as an adapter to link host proteins like CD4 to AP2, leading to their degradation and helping the virus evade immune detection (Lindwasser et al., 2007, J. Virol.). While no drugs are currently FDA-approved specifically for this site, it is an active area of research for anti-viral therapies, with experimental small molecules like B9 and DLC27 being developed to block the Nef-AP2 interaction. The structural conservation of this site across different adaptor complexes presents both a therapeutic opportunity and a challenge regarding selectivity and potential systemic toxicity.

Other names

AP-2 dileucine-based signal binding siteAlpha-sigma2 hemicomplex binding pocket[DE]XXXL[LI] motif siteAP2 alpha-sigma2 interface

Competitive inhibition of [DE]XXXL[LI] motif binding to the AP2 alpha-sigma2 interface, preventing cargo recruitment into clathrin-coated vesicles.