Goldstein set out to find proteins interacting with the COOH terminus of a K+ leak channel, KCNK3, and came up with a surprise: 14–3-3β. The group also found that KCNK3 binds β-COP, the COP1 retrieval protein, via a known dibasic motif. Binding of 14–3-3β and β-COP to KCNK3 was mutually exclusive. Deletion of the last residue of the 14–3-3β binding site led to retention of all KCNK3 protein in the ER, but surface expression was rescued by a further mutation of the dibasic β-COP binding sequence.
A similar system was demonstrated for another leak channel, an acetylcholine receptor subunit, and an MHC-associated protein. Others had individual clues in these systems about trafficking and the binding of 14–3-3 and β-COP, but Goldstein's group is the first to put the whole story together.
For KCNK3, hormonal signals that turn on PKA may trigger the binding of 14–3-3β to the phosphorylated channel subunit, thus increasing surface expression and decreasing the excitability of the cell. Goldstein now wants to know if such a mechanism for controlling surface expression levels is common, and what proteins act with 14–3-3 to release the grip of ER retention. ▪