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

KE Chen; Q Guo; TA Hill; Y Cui; AK Kendall; Z Yang; RJ Hall; MD Healy; J Sacharz; SJ Norwood; S Fonseka; B Xie; RC Reid; N Leneva; RG Parton; R Ghai; DA Stroud; DP Fairlie; H Suga; LP Jackson; RD Teasdale; T Passioura; BM Collins

Journal article

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

KE Chen, Q Guo, TA Hill, Y Cui, AK Kendall, Z Yang, RJ Hall, MD Healy, J Sacharz, SJ Norwood, S Fonseka, B Xie, RC Reid, N Leneva, RG Parton, R Ghai, DA Stroud, DP Fairlie, H Suga, LP Jackson Show all

Science Advances | Published : 2021

DOI: 10.1126/sciadv.abg4007

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Abstract

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..

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University of Melbourne Researchers

David Stroud Author

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Awarded by National Institute of General Medical Sciences

Funding Acknowledgements

This work is supported by funds from the Australian Research Council (ARC) (DP160101743, DP180103244, and CE140100011), National Health and Medical Research Council (NHMRC) (APP1156493 and APP1156732), and Bright Focus Foundation (A2018627S). B.M.C. is supported by an NHMRC Senior Research Fellowship (APP1136021), D.P.F. is supported by an NHMRC Senior Principal Research Fellowship (1117017), R.G.P. is supported by an NHMRC Senior Principal Research Fellowship (APP1058565) and by the Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, and D.A.S. is supported by an NHMRC Career Development Fellowship (APP1140851). This work was also supported by the Japan Agency for Medical Research and Development (AMED), Platform Project for Supporting Drug Discovery and Life Science Research (JP20am0101090), and the Japan Society for the Promotion of Science (JSPS), Specially Promoted Research (JP20H05618) to H.S. Some of this work was performed at the National Center for Cryo-EM Access and Training (NCCAT) and the Simons Electron Microscopy Center located at the New York Structural Biology Center, supported by the NIH Common Fund Transformative High Resolution Cryo-Electron Microscopy program (U24 GM129539), and by grants from the Simons Foundation (SF349247) and NY State Assembly. A.K.K., B.X., and L.P.J. are supported by NIH R35GM119525. L.P.J. is a Pew Scholar in the Biomedical Sciences, supported by the Pew Charitable Trusts.