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Elife. 2016 Dec 7;5. pii: e21301. doi: 10.7554/eLife.21301.

Multiple selection filters ensure accurate tail-anchored membrane protein targeting.

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Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, United States.
Howard Hughes Medical Institute, University of California, San Francisco, United States.
Department of Biochemistry and Biophysics, University of California, San Francisco, United States.


Accurate protein localization is crucial to generate and maintain organization in all cells. Achieving accuracy is challenging, as the molecular signals that dictate a protein's cellular destination are often promiscuous. A salient example is the targeting of an essential class of tail-anchored (TA) proteins, whose sole defining feature is a transmembrane domain near their C-terminus. Here we show that the Guided Entry of Tail-anchored protein (GET) pathway selects TA proteins destined to the endoplasmic reticulum (ER) utilizing distinct molecular steps, including differential binding by the co-chaperone Sgt2 and kinetic proofreading after ATP hydrolysis by the targeting factor Get3. Further, the different steps select for distinct physicochemical features of the TA substrate. The use of multiple selection filters may be general to protein biogenesis pathways that must distinguish correct and incorrect substrates based on minor differences.


ATPase; S. cerevisiae; biochemistry; biological fidelity; cell biology; fluorescence spectroscopy; guided entry of tail anchored proteins; protein targeting and translocation

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