A Tandem Di-hydrophobic Motif Mediates Clathrin-dependent Endocytosis via Direct Binding to the AP-2 alpha sigma 2 Subunits

作者：Ortega Bernardo; Mason Amanda K; Welling Paul A^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2012, 287(32): 26867-26875.

DOI：10.1074/jbc.M112.341990

Select plasma membrane proteins can be marked as cargo for inclusion into clathrin-coated pits by common internalization signals (e. g. Y Chi Chi Phi, dileucine motifs, NPXY) that serve as universal recognition sites for the AP-2 adaptor complex or other clathrin-associated sorting proteins. However, some surface proteins, such as the Kir2.3 potassium channel, lack canonical signals but are still targeted for clathrin-dependent endocytosis. Here, we explore the mechanism. We found an unusual endocytic signal in Kir2.3 that is based on two consecutive pairs of hydrophobic residues. Characterized by the sequence Phi Phi Chi Phi Phi (a tandem di-hydrophobic (TDH) motif, where Phi is a hydrophobic amino acid), the signal shows no resemblance to other endocytic motifs, yet it directly interacts with AP-2 to target the Kir2.3 potassium channel into the endocytic pathway. We found that the tandem di-hydrophobic motif directly binds to the alpha sigma 2 subunits of AP-2, interacting within a large hydrophobic cleft that encompasses part of the docking site for di-Leu signals, but includes additional structures. These observations expand the repertoire of clathrin-dependent internalization signals and the ways in which AP-2 can coordinate endocytosis of cargo proteins.

• 出版日期2012-8-3