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J Cell Sci. 2018 Apr 16. pii: jcs.211110. doi: 10.1242/jcs.211110. [Epub ahead of print]

The GET pathway can increase the risk of mitochondrial outer membrane proteins to be mistargeted to the ER.

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Interfaculty Institute of Biochemistry, University of Tübingen, 72076 Tübingen, Germany.
Centre for Plant Molecular Biology, Developmental Genetics, University of Tübingen, Tübingen, Germany.
Consiglio Nazionale delle Ricerche Institute of Neuroscience, Milan, Italy.
Department of Molecular Biology, Universitätsmedizin Göttingen, Göttingen 37073, Germany.
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.
Interfaculty Institute of Biochemistry, University of Tübingen, 72076 Tübingen, Germany


Tail-anchored (TA) proteins are anchored to their corresponding membrane via a single transmembrane segment (TMS) at their C-terminus. In yeast, the targeting of TA proteins to the endoplasmic reticulum (ER) can be mediated by the guided entry of TA proteins (GET) pathway, whereas it is not yet clear how mitochondrial TA proteins are targeted to their destination. It is widely observed that some mitochondrial outer membrane (OM) proteins are mistargeted to the ER when overexpressed or when their targeting signal is masked. However, the mechanism of this erroneous sorting is currently unknown. In this study, we demonstrate the involvement of the GET machinery in mistargeting of non-optimal mitochondrial OM proteins to the ER. These findings suggest that the GET machinery can, in principle, recognize and guide mitochondrial and non-canonical TA proteins. Hence, under normal conditions, an active mitochondrial targeting pathway must exist that dominates the kinetic competition against other pathways.


ER; GET; Mitochondria; Outer membrane; Protein sorting; Tail-anchor


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