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Tail-anchor targeting by a Get3 tetramer: the structure of an archaeal homologue

Suloway, Christian J. M. and Rome, Michael E. and Clemons, William M., Jr. (2012) Tail-anchor targeting by a Get3 tetramer: the structure of an archaeal homologue. EMBO Journal, 31 (3). pp. 707-719. ISSN 0261-4189. PMCID PMC3273380.

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Efficient delivery of membrane proteins is a critical cellular process. The recently elucidated GET (Guided Entry of TA proteins) pathway is responsible for the targeted delivery of tail-anchored (TA) membrane proteins to the endoplasmic reticulum. The central player is the ATPase Get3, which in its free form exists as a dimer. Biochemical evidence suggests a role for a tetramer of Get3. Here, we present the first crystal structure of an archaeal Get3 homologue that exists as a tetramer and is capable of TA protein binding. The tetramer generates a hydrophobic chamber that we propose binds the TA protein. We use small-angle X-ray scattering to provide the first structural information of a fungal Get3/TA protein complex showing that the overall molecular envelope is consistent with the archaeal tetramer structure. Moreover, we show that this fungal tetramer complex is capable of TA insertion. This allows us to suggest a model where a tetramer of Get3 sequesters a TA protein during targeting to the membrane.

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Clemons, William M., Jr.0000-0002-0021-889X
Additional Information:© 2012 European Molecular Biology Organization. Received 3 May 2011; Accepted 9 November 2011. published online: 29 November 2011. We thank Grace Wu for help generating the TA protein constructs and Shu-ou Shan and Raymond Liu for help in microsome preparation. We thank DC Rees, JW Chartron, S Tanaka, HB Gristick and SO Shan for critical reading of the manuscript. We thank members of the laboratory for support and useful discussions. T. kodakaraensis genomic DNA was kindly provided by Tom Santangelo (Ohio State). We thank Graeme Card, Ana Gonzalez and Michael Soltice for help with data collection at SSRL BL12-2, Justin Chartron, Michael Becker and Craig Ogata for help with data collection at APS GM/ CA CAT BL23ID-D, and Tsutomu Matsui and Hiro Tsuruta for help with data collection and processing at the bioSAXS SSRL BL4-2. ICP-MS instrumentation was provided by the Environmental Analysis Center at the Caltech and we were aided by Nathan Dalleska. We are grateful to Gordon and Betty Moore for support of the Molecular Observatory at Caltech. Operations at SSRL and APS are supported by the US DOE and NIH. This work is funded by grants to WMC including, the Searle Scholar program, a Burroughs- Wellcome Fund Career Award for the Biological Sciences and a National Institutes of Health Grant R01 GM097572. The atomic coordinates and structure factors have been deposited in the RCSB Protein Data Bank, (PDB ID codes 3UG6 and 3UG7 for the P21 and P2 forms, respectively). Author contributions: CJMS performed all of the experiments except the in-vitro translation insertion assay. MER provided microsome membranes and performed the in-vitro translation insertion assay. CJMS and WMC designed experiments and wrote the manuscript. The authors declare that they have no conflict of interest.
Funding AgencyGrant Number
Gordon and Betty Moore FoundationUNSPECIFIED
Department of Energy (DOE)UNSPECIFIED
Searle Scholars ProgramUNSPECIFIED
Burroughs-Wellcome FundUNSPECIFIED
NIHR01 GM097572
Subject Keywords:Arr4p; bioSAXS; GET pathway; protein transport; TRC40
Issue or Number:3
PubMed Central ID:PMC3273380
Record Number:CaltechAUTHORS:20120328-094026313
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Official Citation:Tail-anchor targeting by a Get3 tetramer: the structure of an archaeal homologue Christian JM Suloway, Michael E Rome and William M Clemons Jr The EMBO Journal (2012), 31, - 707 - 719, doi:10.1038/emboj.2011.433
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:29874
Deposited By: Ruth Sustaita
Deposited On:28 Mar 2012 17:45
Last Modified:03 Oct 2019 03:45

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