Mechanism and evolution of the Zn-fingernail required for interaction of VARP with VPS29

Harriet Crawley-Snowdon, Ji-Chun Yang, Nathan R. Zaccai, Luther J. Davis, Lena Wartosch, Emily K. Herman, Nicholas A. Bright, James S. Swarbrick, Brett M. Collins, Lauren P. Jackson, Matthew N. J. Seaman, J. Paul Luzio (), Joel B. Dacks (), David Neuhaus () and David J. Owen ()
Additional contact information
Harriet Crawley-Snowdon: MRC Laboratory of Molecular Biology Cambridge Biomedical Campus
Ji-Chun Yang: MRC Laboratory of Molecular Biology Cambridge Biomedical Campus
Nathan R. Zaccai: CIMR, The Keith Peters Building
Luther J. Davis: CIMR, The Keith Peters Building
Lena Wartosch: CIMR, The Keith Peters Building
Emily K. Herman: University of Alberta
Nicholas A. Bright: CIMR, The Keith Peters Building
James S. Swarbrick: Pharmacology and Therapeutics, The University of Melbourne
Brett M. Collins: The University of Queensland, Institute for Molecular Bioscience
Lauren P. Jackson: CIMR, The Keith Peters Building
Matthew N. J. Seaman: CIMR, The Keith Peters Building
J. Paul Luzio: CIMR, The Keith Peters Building
Joel B. Dacks: University of Alberta
David Neuhaus: MRC Laboratory of Molecular Biology Cambridge Biomedical Campus
David J. Owen: CIMR, The Keith Peters Building

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract VARP and TBC1D5 are accessory/regulatory proteins of retromer-mediated retrograde trafficking from endosomes. Using an NMR/X-ray approach, we determined the structure of the complex between retromer subunit VPS29 and a 12 residue, four-cysteine/Zn++ microdomain, which we term a Zn-fingernail, two of which are present in VARP. Mutations that abolish VPS29:VARP binding inhibit trafficking from endosomes to the cell surface. We show that VARP and TBC1D5 bind the same site on VPS29 and can compete for binding VPS29 in vivo. The relative disposition of VPS29s in hetero-hexameric, membrane-attached, retromer arches indicates that VARP will prefer binding to assembled retromer coats through simultaneous binding of two VPS29s. The TBC1D5:VPS29 interaction is over one billion years old but the Zn-fingernail appears only in VARP homologues in the lineage directly giving rise to animals at which point the retromer/VARP/TBC1D5 regulatory network became fully established.

Date: 2020
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DOI: 10.1038/s41467-020-18773-2

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