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De novo macrocyclic peptides for inhibiting, stabilizing, and probing the function of the retromer endosomal trafficking complex

The retromer complex (Vps35-Vps26-Vps29) is essential for endosomal membrane trafficking and signaling. Mutation of the retromer subunit Vps35 causes late-onset Parkinson’s disease, while viral and bacterial pathogens can hijack the complex during cellular infection. To modulate and probe its functi...

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Autores principales: Chen, Kai-En, Guo, Qian, Hill, Timothy A., Cui, Yi, Kendall, Amy K., Yang, Zhe, Hall, Ryan J., Healy, Michael D., Sacharz, Joanna, Norwood, Suzanne J., Fonseka, Sachini, Xie, Boyang, Reid, Robert C., Leneva, Natalya, Parton, Robert G., Ghai, Rajesh, Stroud, David A., Fairlie, David P., Suga, Hiroaki, Jackson, Lauren P., Teasdale, Rohan D., Passioura, Toby, Collins, Brett M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8635440/
https://www.ncbi.nlm.nih.gov/pubmed/34851660
http://dx.doi.org/10.1126/sciadv.abg4007
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author Chen, Kai-En
Guo, Qian
Hill, Timothy A.
Cui, Yi
Kendall, Amy K.
Yang, Zhe
Hall, Ryan J.
Healy, Michael D.
Sacharz, Joanna
Norwood, Suzanne J.
Fonseka, Sachini
Xie, Boyang
Reid, Robert C.
Leneva, Natalya
Parton, Robert G.
Ghai, Rajesh
Stroud, David A.
Fairlie, David P.
Suga, Hiroaki
Jackson, Lauren P.
Teasdale, Rohan D.
Passioura, Toby
Collins, Brett M.
author_facet Chen, Kai-En
Guo, Qian
Hill, Timothy A.
Cui, Yi
Kendall, Amy K.
Yang, Zhe
Hall, Ryan J.
Healy, Michael D.
Sacharz, Joanna
Norwood, Suzanne J.
Fonseka, Sachini
Xie, Boyang
Reid, Robert C.
Leneva, Natalya
Parton, Robert G.
Ghai, Rajesh
Stroud, David A.
Fairlie, David P.
Suga, Hiroaki
Jackson, Lauren P.
Teasdale, Rohan D.
Passioura, Toby
Collins, Brett M.
author_sort Chen, Kai-En
collection PubMed
description The retromer complex (Vps35-Vps26-Vps29) is essential for endosomal membrane trafficking and signaling. Mutation of the retromer subunit Vps35 causes 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 that most of the 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. Last, tagged peptides can be used to probe the cellular localization of retromer and its functional interactions in cells, providing novel tools for studying retromer function.
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spelling pubmed-86354402021-12-13 De novo macrocyclic peptides for inhibiting, stabilizing, and probing the function of the retromer endosomal trafficking complex Chen, Kai-En Guo, Qian Hill, Timothy A. Cui, Yi Kendall, Amy K. Yang, Zhe Hall, Ryan J. Healy, Michael D. Sacharz, Joanna Norwood, Suzanne J. Fonseka, Sachini Xie, Boyang Reid, Robert C. Leneva, Natalya Parton, Robert G. Ghai, Rajesh Stroud, David A. Fairlie, David P. Suga, Hiroaki Jackson, Lauren P. Teasdale, Rohan D. Passioura, Toby Collins, Brett M. Sci Adv Neuroscience The retromer complex (Vps35-Vps26-Vps29) is essential for endosomal membrane trafficking and signaling. Mutation of the retromer subunit Vps35 causes 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 that most of the 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. Last, tagged peptides can be used to probe the cellular localization of retromer and its functional interactions in cells, providing novel tools for studying retromer function. American Association for the Advancement of Science 2021-12-01 /pmc/articles/PMC8635440/ /pubmed/34851660 http://dx.doi.org/10.1126/sciadv.abg4007 Text en Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Neuroscience
Chen, Kai-En
Guo, Qian
Hill, Timothy A.
Cui, Yi
Kendall, Amy K.
Yang, Zhe
Hall, Ryan J.
Healy, Michael D.
Sacharz, Joanna
Norwood, Suzanne J.
Fonseka, Sachini
Xie, Boyang
Reid, Robert C.
Leneva, Natalya
Parton, Robert G.
Ghai, Rajesh
Stroud, David A.
Fairlie, David P.
Suga, Hiroaki
Jackson, Lauren P.
Teasdale, Rohan D.
Passioura, Toby
Collins, Brett M.
De novo macrocyclic peptides for inhibiting, stabilizing, and probing the function of the retromer endosomal trafficking complex
title De novo macrocyclic peptides for inhibiting, stabilizing, and probing the function of the retromer endosomal trafficking complex
title_full De novo macrocyclic peptides for inhibiting, stabilizing, and probing the function of the retromer endosomal trafficking complex
title_fullStr De novo macrocyclic peptides for inhibiting, stabilizing, and probing the function of the retromer endosomal trafficking complex
title_full_unstemmed De novo macrocyclic peptides for inhibiting, stabilizing, and probing the function of the retromer endosomal trafficking complex
title_short De novo macrocyclic peptides for inhibiting, stabilizing, and probing the function of the retromer endosomal trafficking complex
title_sort de novo macrocyclic peptides for inhibiting, stabilizing, and probing the function of the retromer endosomal trafficking complex
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8635440/
https://www.ncbi.nlm.nih.gov/pubmed/34851660
http://dx.doi.org/10.1126/sciadv.abg4007
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