Short length transmembrane domains having voluminous exoplasmic halves determine retention of Type II membrane proteins in the Golgi complex

It is still unclear why some proteins that travel along the secretory pathway are retained in the Golgi complex while others follow their way to the plasma membrane (PM). Recent bioinformatic analyses on a large number of single spanning membrane proteins support the hypothesis that specific features of the Trans-Membrane Domain (TMD) are relevant to the sorting of these proteins to particular organelles. Here we experimentally test this hypothesis for Golgi and PM proteins. Using the Golgi SNARE Sft1 and the PM SNARE Sso1 from Saccharomyces cerevisiae as model proteins, we modified the length of their TMDs and the volume of their exoplasmic hemi-TMD, and determined their subcellular localization both in yeast and mammalian cells. We found that short TMDs with voluminous exoplasmic hemi-TMDs confer Golgi membrane residence, while TMDs having less voluminous exoplasmic hemi-TMDs, being either short or long, confer PM residence to these proteins. Results indicate that the shape of the exoplasmic hemi-TMD, in addition to the length of the entire TMD, determine retention in the Golgi or exit to the PM of Type II membrane proteins.