Hydrophobic mismatch-induced clustering as a primer for protein sorting in the secretory pathway.

Sorting of transmembrane proteins is a central task of the secretory pathway. Due to the lack of an organizing mastermind, the decision whether a protein participates in anterograde/retrograde transport or rather stays in its compartment has to be made by a self-organization process on the molecular scale. Minimizing the hydrophobic mismatch between a protein and the surrounding lipid bilayer has been shown to be an important determinant of protein localization. It has remained elusive, however, how mislocalized proteins sense that remote organelles may provide a better lipid environment, i.e. how proteins differentially control their journey along the secretory pathway. Here we show by coarse-grained membrane simulations that proteins partition into the lipid phase with the smallest hydrophobic mismatch on heterogeneous membranes while they cluster and even segregate as homo-oligomers according to their hydrophobic mismatch on a homogeneous bilayer. We propose that protein sorting is facilitated by stabilizing coat proteins at clusters of mislocalized proteins that experience a hydrophobic mismatch.