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The client-binding domain of the cochaperone SGTA/Sgt2 has a helical-hand structure that binds a short hydrophobic helix

Lin, Ku-Feng and Fry, Michelle and Saladi, Shyam and Clemons, William M., Jr. (2019) The client-binding domain of the cochaperone SGTA/Sgt2 has a helical-hand structure that binds a short hydrophobic helix. . (Unpublished)

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The correct targeting and insertion of tail-anchored (TA) integral membrane proteins (IMP) is critical for cellular homeostasis. The mammalian protein SGTA, and its fungal homolog Sgt2 (Sgt2/A), binds hydrophobic clients and is the entry point for targeting of ER-bound TA IMPs. Here we reveal molecular details that underlie the mechanism of Sgt2/A binding to TA clients. We establish that the Sgt2/A C-terminal region is conserved but flexible, sufficient for client binding, and has functional and structural similarity to the DP domains of Sti1. A molecular model for Sgt2/A-C reveals a helical hand forming a hydrophobic groove, consistent with a higher affinity for TA clients with hydrophobic faces and a minimal length of 11 residues. Finally, we show that a hydrophobic face metric improves the predictions for TA localization in vivo. The structure and binding mechanism positions Sgt2/A into a broader class of helical-hand domains that reversibly bind hydrophobic clients.

Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription Paper Paper
Saladi, Shyam0000-0001-9701-3059
Clemons, William M., Jr.0000-0002-0021-889X
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license. bioRxiv preprint first posted online Jan. 10, 2019. We thank D. G. VanderVelde for assistance with NMR data collection; S. Mayo for providing computing resources; S.-o. Shan, H. J. Cho, and members of the Clemons lab for support and discussion. We thank J.-Y. Mock and A. M. Thinn for comments on the manuscript. This work was supported by the National Institutes of Health (NIH) Pioneer Award 5DP1GM105385 and Grant R01GM097572 (to WMC), NIH/National Research Service Award Training Grant 5T32GM07616 (to SMS and MYF), and a National Science Foundation Graduate Research fellowship under Grant 1144469 (to SMS). Data and Code Availability: All configuration, analysis, and figure generation code employed is available openly at with analysis done in Jupyter Lab/Notebooks using Python 3.6 enabled by Numpy, Pandas, Scikit-Learn, BioPython, and Bokeh [106-111]. The system topology and output files (including trajectory sampled at 0.5 ns intervals) can be permanently found here: 10.22002/D1.1100.
Funding AgencyGrant Number
NIH Predoctoral Fellowship5T32GM07616
NSF Graduate Research FellowshipDGE-1144469
Subject Keywords:Tail-anchored proteins, Protein targeting, co-chaperones, Ubiquilins, Sti1, Hop
Record Number:CaltechAUTHORS:20190114-075410952
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Official Citation:The client-binding domain of the cochaperone SGTA/Sgt2 has a helical-hand structure that binds a short hydrophobic helix. Ku-Feng Lin, Michelle Y Fry, Shyam Saladi, William M Clemons Jr. bioRxiv 517573; doi:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:92239
Deposited By: Tony Diaz
Deposited On:14 Jan 2019 21:01
Last Modified:03 Oct 2019 20:42

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