The sorting of a small potassium channel in mammalian cells can be shifted between mitochondria and plasma membrane

•Two similar viral K+ channels are sorted to either mitochondria or plasma membrane.•A N-terminal mitochondrial sorting signal is neither necessary nor sufficient for mitochondrial sorting.•The mitochondria associated membranes (MAMs) are not involved in sorting.•The C-terminus of the channels contains a sorting signal, which decides between trafficking to mitochondria or plasma membrane.

The two small and similar viral K+ channels Kcv and Kesv are sorted in mammalian cells and yeast to different destinations. Analysis of the sorting pathways shows that Kcv is trafficking via the secretory pathway to the plasma membrane, while Kesv is inserted via the TIM/TOM complex to the inner membrane of mitochondria. Studies with Kesv mutants show that an N-terminal mitochondrial targeting sequence in this channel is neither necessary nor sufficient for sorting of Kesv the mitochondria. Instead the sorting of Kesv can be redirected from the mitochondria to the plasma membrane by an insertion of ≥2 amino acids in a position sensitive manner into the C-terminal transmembrane domain (TMD2) of this channel. The available data advocate the presence of a C-terminal sorting signal in TMD2 of Kesv channel, which is presumably not determined by the length of this domain.

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