A signal comprising a basic cluster and an amphipathic alpha-helix interacts with lipids and is required for the transport of Ist2 to the yeast cortical ER.

The yeast integral membrane protein Ist2 is encoded by a bud-localised mRNA and accumulates at patch-like domains of the cell periphery, either at the cortical ER or at ER-associated domains of the plasma membrane. Transport of IST2 mRNA and local protein synthesis are not prerequisite for this localisation, indicating that Ist2 can travel through the general ER to membranes at the cell periphery. Here, we describe that the accumulation of Ist2 at the cortical ER requires a cytosolically exposed complex sorting signal that can interact with lipids at the yeast plasma membrane. Binding of the Ist2 sorting signal to lipids and rapid and efficient transport of Ist2 from perinuclear to cortical ER depend on a cluster of lysine residues, the formation of an amphipathic alpha-helix and a patch of hydrophobic side chains positioned at one side of the amphipathic alpha-helix. We suggest that a direct interaction of the Ist2 sorting signal with lipids at the plasma membrane places Ist2 at contact sites between cortical ER and plasma membrane. This provides a physical link of an integral membrane protein of the cortical ER with the plasma membrane and might allow direct transport of proteins from cortical ER to domains of the plasma membrane.