Abstract
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.
Highlights
Efficient and accurate protein localization is a prerequisite to generate and maintain compartmentalization in all cells
A comprehensive analysis of the Grand Average of Hydropathy (GRAVY) (Kyte and Doolittle, 1982) scores of TAs shows that: (i) the transmembrane domains (TMDs) of TAs span a wide range of hydrophobicity (Figure 1, GRAVY Score); (ii) among these, established Guided Entry of Tail-anchored protein (GET) substrates (Mateja et al, 2015; Schuldiner et al, 2008) (Figure 1A, highlighted in black) are enriched in the range of higher hydrophobicity; (iii) mitochondrial TAs tend to span a range of lower hydrophobicity, but exhibit significant overlap with that of GET substrates (Figure 1B vs. 1A)
To understand how TA substrates are selectively targeted to the endoplasmic reticulum (ER), we established a set of model TAs in which we independently varied the TMD and the C-terminal element (CTE)
Summary
Efficient and accurate protein localization is a prerequisite to generate and maintain compartmentalization in all cells. Understanding how protein-targeting pathways achieve accurate membrane protein localization has been challenging for multiple reasons. Minor differences in targeting signals distinguish proteins that belong to alternative pathways or organelles (Emanuelsson and von Heijne, 2001; von Heijne, 1985; Zhang and Shan, 2014; Zheng and Gierasch, 1996). Protein-targeting pathways must evolve robust selection mechanisms that can detect these minor differences. Except for a few systems (see [Randall and Hardy, 1995; Zhang and Shan, 2014]), the molecular mechanisms by which protein targeting machineries overcome these challenges are not well understood for most pathways
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
