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Published November 2021 | Published
Journal Article Open

Subunit cooperation in the Get1/2 receptor promotes tail-anchored membrane protein insertion


The guided entry of tail-anchored protein (GET) pathway, in which the Get3 ATPase delivers an essential class of tail-anchored membrane proteins (TAs) to the Get1/2 receptor at the endoplasmic reticulum, provides a conserved mechanism for TA biogenesis in eukaryotic cells. The membrane-associated events of this pathway remain poorly understood. Here we show that complex assembly between the cytosolic domains (CDs) of Get1 and Get2 strongly enhances the affinity of the individual subunits for Get3•TA, thus enabling efficient capture of the targeting complex. In addition to the known role of Get1CD in remodeling Get3 conformation, two molecular recognition features (MoRFs) in Get2CD induce Get3 opening, and both subunits are required for optimal TA release from Get3. Mutation of the MoRFs attenuates TA insertion into the ER in vivo. Our results demonstrate extensive cooperation between the Get1/2 receptor subunits in the capture and remodeling of the targeting complex, and emphasize the role of MoRFs in receptor function during membrane protein biogenesis.

Additional Information

© 2021 Chio et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). Submitted: 12 March 2021; Revised: 3 August 2021; Accepted: 19 August 2021. We thank Vladimir Denic for the mini-Get1/2 construct, Jennifer Keefe for help with SEC-MALS, and members of the Shan laboratory for general discussion and comments on the manuscript. This work was supported by Dean Willard Chair funds to S. Weiss and National Institutes of Health grants R01 GM107368 and R35 GM136321 and the Gordon and Betty Moore Foundation grant GBMF2939 to S.-o. Shan. The authors declare no competing financial interests. Author contributions: U.S. Chio, Y. Liu, and S.-o. Shan designed research; U.S. Chio, Y. Liu, W.J. Shim, and S. Chandrasekar performed biochemical experiments; U.S. Chio and Y. Liu analyzed biochemical data with input from S.-o. Shan; U.S. Chio, Y. Liu, and SY. Chung performed sm fluorescence experiments; U.S. Chio, Y. Liu, and SY. Chung analyzed biophysics data with input from S. Weiss and S.-o. Shan; U.S. Chio, Y. Liu, and S.-o. Shan wrote the manuscript; SY. Chung and S. Weiss revised the manuscript. All authors approved the final manuscript. U.S. Chio and Y. Liu contributed equally to this paper.

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August 20, 2023
October 23, 2023