Lateral plasma membrane compartmentalization links protein function and turnover

Biological membranes organize their proteins and lipids into nano- and microscale patterns. In the yeast plasma membrane (PM) constituents segregate into a large number of distinct domains. However, if and how this intricate patchwork contributes to biological functions at the PM is still poorly understood. Here, we reveal an elaborate interplay between PM compartmentalization, biochemical function and endocytic turnover. Using the methionine permease Mup1 as model system we demonstrate that this transporter segregates into PM clusters. Clustering requires sphingolipids, the tetraspanner Nce102 and TORC2 signaling. Importantly, we show that during substrate transport, a simple conformational change in Mup1 mediates rapid relocation into a unique disperse network at the PM. Clustered Mup1 is protected from turnover, whereas relocated Mup1 actively recruits the endocytic machinery thereby initiating its own turnover. Our findings suggest that lateral compartmentalization provides an important regulatory link between function and turnover of PM proteins.