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Published December 7, 2016 | Published
Journal Article Open

Multiple selection filters ensure accurate tail-anchored membrane protein targeting


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.

Additional Information

© 2016, Rao et al. This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited. Received September 06, 2016; Accepted December 06, 2016; Published December 07, 2016. We thank Bil Clemons, Michael Rome, Kuang Shen, Xin Zhang, and members of the Shan and Clemons labs for critical discussions and comments on the manuscript, and the Dougherty lab for use of their HPLC. This work was supported by NIH grant GM107368 and Gordon and Betty Moore Foundation Grant GBMF2939 to S.S., NIH grants R01GM32384 & U01GM098254 to P.W., NIH training grant 5T32GM007616-33 to M.R, and the Leukemia and Lymphoma Society fellowship to V.O. P.W. is an Investigator of the Howard Hughes Medical Institute. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. The authors declare that no competing interests exist.

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