A novel sorting sequence in the β2-adrenergic receptor switches recycling from default to the Hrs-dependent mechanism

Plasma membrane recycling of G protein-coupled receptors can occur by at least two distinct mechanisms as follows: a default mechanism that occurs nonselectively, and a specifically sorted mechanism that requires the endosome-associated protein Hrs. In this study we have defined a sequence in the beta(2)-adrenergic receptor cytoplasmic tail that confers Hrs dependence on receptor recycling. This sequence resembles acidic dileucine class motifs found in other membrane proteins but is structurally and functionally distinct from previously identified sorting sequences. Mutation of the novel sorting sequence rendered plasma membrane recycling independent of Hrs and independent of a distal PDZ ligand required for Hrs-dependent recycling. We propose that the novel sorting sequence functions to switch endocytic trafficking between mechanistically distinct recycling modes, thereby explaining failure of the wild type beta(2)-adrenergic receptor to recycle efficiently by default.