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Sequence-based features that are determinant for tail-anchored membrane protein sorting in eukaryotes

Fry, Michelle Y. and Saladi, Shyam M. and Cunha, Alexandre and Clemons, William M., Jr. (2021) Sequence-based features that are determinant for tail-anchored membrane protein sorting in eukaryotes. Traffic, 22 (9). pp. 306-318. ISSN 1398-9219. PMCID PMC8380732. doi:10.1111/tra.12809.

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The correct targeting and insertion of tail-anchored (TA) integral membrane proteins is critical for cellular homeostasis. TA proteins are defined by a hydrophobic transmembrane domain (TMD) at their C-terminus and are targeted to either the ER or mitochondria. Derived from experimental measurements of a few TA proteins, there has been little examination of the TMD features that determine localization. As a result, the localization of many TA proteins are misclassified by the simple heuristic of overall hydrophobicity. Because ER-directed TMDs favor arrangement of hydrophobic residues to one side, we sought to explore the role of geometric hydrophobic properties. By curating TA proteins with experimentally determined localizations and assessing hypotheses for recognition, we bioinformatically and experimentally verify that a hydrophobic face is the most accurate singular metric for separating ER and mitochondria-destined yeast TA proteins. A metric focusing on an 11 residue segment of the TMD performs well when classifying human TA proteins. The most inclusive predictor uses both hydrophobicity and C-terminal charge in tandem. This work provides context for previous observations and opens the door for more detailed mechanistic experiments to determine the molecular factors driving this recognition.

Item Type:Article
Related URLs:
URLURL TypeDescription Review ItemCode
Fry, Michelle Y.0000-0002-3209-5492
Saladi, Shyam M.0000-0001-9701-3059
Cunha, Alexandre0000-0002-2541-6024
Clemons, William M., Jr.0000-0002-0021-889X
Additional Information:© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Issue Online: 19 August 2021; Version of Record online: 03 August 2021; Accepted manuscript online: 21 July 2021; Manuscript accepted: 18 July 2021; Manuscript revised: 15 July 2021; Manuscript received: 04 May 2021. Funding information: National Science Foundation Graduate Research, Grant/Award Number: 1144469; NIH/National Research Service Award Training, Grant/Award Number: 5T32GM07616; National Institutes of Health, Grant/Award Number: R01GM097572. Peer Review: The peer review history for this article is available at Data Availability Statement: All code employed is available openly at with analysis done in Jupyter Lab/Notebooks using Python 3.6 enabled by Numpy, Pandas, Scikit-Learn, BioPython, bebi103, and Bokeh as well as in Rstudio/Rmarkdown Notebooks enabled by packages within the Tidyverse ecosystem.
Funding AgencyGrant Number
NSF Graduate Research FellowshipDGE-1144469
NIH Predoctoral Fellowship5T32GM07616
Subject Keywords:co-chaperones; EMC; GET pathway; protein targeting; SND pathway; tail-anchored proteins
Issue or Number:9
PubMed Central ID:PMC8380732
Record Number:CaltechAUTHORS:20210729-215854560
Persistent URL:
Official Citation:Fry, MY, Saladi, SM, Cunha, A, Clemons, WM. Sequence-based features that are determinant for tail-anchored membrane protein sorting in eukaryotes. Traffic. 2021; 22( 9): 306- 318.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:110084
Deposited By: Tony Diaz
Deposited On:02 Aug 2021 17:20
Last Modified:24 Aug 2021 17:06

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