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Molecular basis of the TRAP complex function in ER protein biogenesis

View ORCID ProfileMateusz Jaskolowski, View ORCID ProfileAhmad Jomaa, View ORCID ProfileMartin Gamerdinger, Sandeep Shrestha, Marc Leibundgut, View ORCID ProfileElke Deuerling, View ORCID ProfileNenad Ban
doi: https://doi.org/10.1101/2022.10.04.510795
Mateusz Jaskolowski
1Department of Biology, Institute of Molecular Biology and Biophysics, ETH Zurich, 8093 Zurich, Switzerland
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  • ORCID record for Mateusz Jaskolowski
Ahmad Jomaa
1Department of Biology, Institute of Molecular Biology and Biophysics, ETH Zurich, 8093 Zurich, Switzerland
3Department of Molecular Physiology and Biological Physics and the Centre for Cell and Membrane Physiology, University of Virginia, 22903 Charlottesville, USA
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  • For correspondence: ban@mol.biol.ethz.ch elke.deuerling@uni-konstanz.de ahmadjomaa@virginia.edu
Martin Gamerdinger
2Department of Biology, Molecular Microbiology, University of Konstanz, 78457 Konstanz, Germany
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Sandeep Shrestha
2Department of Biology, Molecular Microbiology, University of Konstanz, 78457 Konstanz, Germany
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Marc Leibundgut
1Department of Biology, Institute of Molecular Biology and Biophysics, ETH Zurich, 8093 Zurich, Switzerland
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Elke Deuerling
2Department of Biology, Molecular Microbiology, University of Konstanz, 78457 Konstanz, Germany
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  • For correspondence: ban@mol.biol.ethz.ch elke.deuerling@uni-konstanz.de ahmadjomaa@virginia.edu
Nenad Ban
1Department of Biology, Institute of Molecular Biology and Biophysics, ETH Zurich, 8093 Zurich, Switzerland
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  • For correspondence: ban@mol.biol.ethz.ch elke.deuerling@uni-konstanz.de ahmadjomaa@virginia.edu
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ABSTRACT

The Translocon Associated Protein (TRAP) complex resides in the endoplasmic reticulum (ER) membrane and interacts with the Sec translocon and the translating ribosome to facilitate biogenesis of secretory and membrane proteins1–4. TRAP is essential for the secretion of many hormones, and its key role in the production of the hormone peptide insulin has been particularly well established5,6. The mechanism by which TRAP engages ribosomes and the translocon to facilitate translocation of protein clients in the secretory pathway is not clear. Here, we reveal the molecular architecture of the mammalian TRAP complex and how it engages the translating ribosome associated with Sec61 translocon on the ER membrane. The TRAP complex is anchored to the ribosome via a long tether and its position relative to the ribosome and the translocon is further stabilized by a finger-like loop. This spatial arrangement positions a cradle-like lumenal domain of TRAP below the protein conducting pore of the translocon for interactions with translocated nascent chains. The biological importance of these key interactions is evident by structure-guided TRAP mutations in C. elegans that lead to growth deficits associated with increased ER stress and defects in insulin secretion. Our findings elucidate the molecular basis of the TRAP complex in the biogenesis and translocation of proteins at the ER.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
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-NC-ND 4.0 International license.
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Posted October 04, 2022.
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Molecular basis of the TRAP complex function in ER protein biogenesis
Mateusz Jaskolowski, Ahmad Jomaa, Martin Gamerdinger, Sandeep Shrestha, Marc Leibundgut, Elke Deuerling, Nenad Ban
bioRxiv 2022.10.04.510795; doi: https://doi.org/10.1101/2022.10.04.510795
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Molecular basis of the TRAP complex function in ER protein biogenesis
Mateusz Jaskolowski, Ahmad Jomaa, Martin Gamerdinger, Sandeep Shrestha, Marc Leibundgut, Elke Deuerling, Nenad Ban
bioRxiv 2022.10.04.510795; doi: https://doi.org/10.1101/2022.10.04.510795

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