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De novo macrocyclic peptides for inhibiting, stabilising and probing the function of the Retromer endosomal trafficking complex

View ORCID ProfileKai-En Chen, Qian Guo, Yi Cui, Amy K. Kendall, Timothy A. Hill, View ORCID ProfileRyan J. Hall, Joanna Sacharz, Suzanne J. Norwood, View ORCID ProfileBoyang Xie, View ORCID ProfileNatalya Leneva, View ORCID ProfileZhe Yang, View ORCID ProfileRajesh Ghai, View ORCID ProfileDavid A. Stroud, David Fairlie, View ORCID ProfileHiroaki Suga, View ORCID ProfileLauren P. Jackson, View ORCID ProfileRohan D. Teasdale, View ORCID ProfileToby Passioura, View ORCID ProfileBrett M. Collins
doi: https://doi.org/10.1101/2020.12.03.410779
Kai-En Chen
1The University of Queensland, Institute for Molecular Bioscience, St. Lucia, Queensland, 4072, Australia
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Qian Guo
1The University of Queensland, Institute for Molecular Bioscience, St. Lucia, Queensland, 4072, Australia
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Yi Cui
2The University of Queensland, School of Biomedical Sciences, St Lucia, Queensland, 4072, Australia
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Amy K. Kendall
3Department of Biological Sciences, Vanderbilt University, Nashville, TN 37232, USA
4Center for Structural Biology, Vanderbilt University, Nashville, TN 37232, USA
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Timothy A. Hill
5ARC Centre of Excellence for Innovations in Peptide and Protein Science, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Qld 4072, Australia
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Ryan J. Hall
1The University of Queensland, Institute for Molecular Bioscience, St. Lucia, Queensland, 4072, Australia
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Joanna Sacharz
6Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, 3052 Victoria, Australia
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Suzanne J. Norwood
1The University of Queensland, Institute for Molecular Bioscience, St. Lucia, Queensland, 4072, Australia
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Boyang Xie
3Department of Biological Sciences, Vanderbilt University, Nashville, TN 37232, USA
4Center for Structural Biology, Vanderbilt University, Nashville, TN 37232, USA
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Natalya Leneva
1The University of Queensland, Institute for Molecular Bioscience, St. Lucia, Queensland, 4072, Australia
6Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, 3052 Victoria, Australia
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Zhe Yang
2The University of Queensland, School of Biomedical Sciences, St Lucia, Queensland, 4072, Australia
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Rajesh Ghai
1The University of Queensland, Institute for Molecular Bioscience, St. Lucia, Queensland, 4072, Australia
7Cambridge Institute for Medical Research, Cambridge, CB2 0XY, UK
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David A. Stroud
6Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, 3052 Victoria, Australia
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David Fairlie
5ARC Centre of Excellence for Innovations in Peptide and Protein Science, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Qld 4072, Australia
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Hiroaki Suga
8CSL Ltd, Parkville, Victoria, 3052, Australia
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Lauren P. Jackson
3Department of Biological Sciences, Vanderbilt University, Nashville, TN 37232, USA
4Center for Structural Biology, Vanderbilt University, Nashville, TN 37232, USA
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Rohan D. Teasdale
2The University of Queensland, School of Biomedical Sciences, St Lucia, Queensland, 4072, Australia
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Toby Passioura
8CSL Ltd, Parkville, Victoria, 3052, Australia
9Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo 113-0033, Japan
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Brett M. Collins
1The University of Queensland, Institute for Molecular Bioscience, St. Lucia, Queensland, 4072, Australia
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  • For correspondence: b.collins@imb.uq.edu.au
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ABSTRACT

The Retromer complex (Vps35-Vps26-Vps29) is essential for endosomal membrane trafficking and signalling. Mutations in Retromer cause late-onset Parkinson’s disease, while viral and bacterial pathogens can hijack the complex during cellular infection. To modulate and probe its function we have created a novel series of macrocyclic peptides that bind Retromer with high affinity and specificity. Crystal structures show the majority of cyclic peptides bind to Vps29 via a Pro-Leu-containing sequence, structurally mimicking known interactors such as TBC1D5, and blocking their interaction with Retromer in vitro and in cells. By contrast, macrocyclic peptide RT-L4 binds Retromer at the Vps35-Vps26 interface and is a more effective molecular chaperone than reported small molecules, suggesting a new therapeutic avenue for targeting Retromer. Finally, tagged peptides can be used to probe the cellular localisation of Retromer and its functional interactions in cells, providing novel tools for studying Retromer function.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

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Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted July 27, 2021.
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De novo macrocyclic peptides for inhibiting, stabilising and probing the function of the Retromer endosomal trafficking complex
Kai-En Chen, Qian Guo, Yi Cui, Amy K. Kendall, Timothy A. Hill, Ryan J. Hall, Joanna Sacharz, Suzanne J. Norwood, Boyang Xie, Natalya Leneva, Zhe Yang, Rajesh Ghai, David A. Stroud, David Fairlie, Hiroaki Suga, Lauren P. Jackson, Rohan D. Teasdale, Toby Passioura, Brett M. Collins
bioRxiv 2020.12.03.410779; doi: https://doi.org/10.1101/2020.12.03.410779
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De novo macrocyclic peptides for inhibiting, stabilising and probing the function of the Retromer endosomal trafficking complex
Kai-En Chen, Qian Guo, Yi Cui, Amy K. Kendall, Timothy A. Hill, Ryan J. Hall, Joanna Sacharz, Suzanne J. Norwood, Boyang Xie, Natalya Leneva, Zhe Yang, Rajesh Ghai, David A. Stroud, David Fairlie, Hiroaki Suga, Lauren P. Jackson, Rohan D. Teasdale, Toby Passioura, Brett M. Collins
bioRxiv 2020.12.03.410779; doi: https://doi.org/10.1101/2020.12.03.410779

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