Adaptor protein complex 2 (AP-2)

Adaptor protein complex 2 (AP-2) is a heterotetrameric assembly consisting of alpha, beta2, mu2, and sigma2 subunits that serves as a central hub for clathrin-mediated endocytosis at the plasma membrane (Conner & Schmid, 2003, Nature). It functions by recognizing YXXΦ and [ED]XXXLL motifs on cargo proteins and coupling them to the clathrin scaffold to facilitate vesicle formation (UniProt, 2024). AP-2 plays a significant role in human disease; for instance, mutations in the AP2S1 subunit reduce the endocytosis of the calcium-sensing receptor (CaSR), leading to Familial Hypocalciuric Hypercalcemia Type 3 (Nesbit et al., 2013, Lancet). Additionally, AP-2 is a key host factor exploited by viruses such as SARS-CoV-2 and HCV for cellular entry (Stebbing et al., 2020, Lancet Infect Dis). Therapeutic strategies include the use of AAK1 inhibitors like Baricitinib, which prevent the phosphorylation of the mu2 subunit (AP2M1), thereby blocking the assembly of the endocytic machinery (Richardson et al., 2020, Lancet Infect Dis). While targeting AP-2 offers potential for antiviral and oncology applications, its essential role in nutrient uptake and synaptic vesicle recycling presents significant safety challenges (Kirchhausen et al., 2014, Annu Rev Cell Dev Biol).

Other names

AP2AP-2Clathrin-associated adaptor protein complex 2Plasma membrane adaptor complexAP-2 complex

Inhibition of clathrin-mediated endocytosis by preventing the recruitment of cargo or the assembly of clathrin-coated pits, often via the inhibition of regulatory kinases like AAK1 (Stebbing et al., 2020).