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

Crawley-Snowdon, Harriet, Yang, Ji-Chun, Zaccai, Nathan R., Davis, Luther J., Wartosch, Lena, Herman, Emily K., Bright, Nicholas A., Swarbrick, James S., Collins, Brett M., Jackson, Lauren P., Seaman, Matthew N. J., Luzio, J. Paul, Dacks, Joel B., Neuhaus, David, Owen, David J.·2020·Nature Communications
DOI 10.1038/s41467-020-18773-2PMC PMC7539009
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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.

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  • AlphaFold2 predicted the association of a conserved surface-exposed hydrophobic cavity on VPS29 (defined by Leu152) with Pro-Leu (PL) motifs from TBC1D5 (141PL142) and VARP (713PL714), and for TBC1D5, the association of an additional 283Ile-Pro-Phe285 hydrophobic motif with VPS35.

    “Consistent with published structural data, AlphaFold2 predicted the association of a conserved surface-exposed hydrophobic cavity on VPS29 (defined by Leu152) with Pro-Leu (PL) motifs from TBC1D5 (141PL142) and VARP (713PL714) and for TBC1D5, the association of an additional 283Ile-Pro-Phe285 hydrophobic motif with VPS35 (Supplementary Fig. 5)77,82.”

    From Mapping of endosomal proximity proteomes reveals Retromer as a hub for RAB GTPase regulation (2025) · cites this paper as [82]

  • The Retromer proximity proteome has highlighted a close association with regulators of small GTPases, including well-established Retromer accessory proteins TBC1D5 and ANKRD27.

    “The Retromer proximity proteome has highlighted a close association with regulators of small GTPases, including well-established Retromer accessory proteins TBC1D5 and ANKRD2777,82.”

    From Mapping of endosomal proximity proteomes reveals Retromer as a hub for RAB GTPase regulation (2025) · cites this paper as [82]

  • The Retromer sub-domain proximity proteome included the RAB7 GAP TBC1D5, the RAB21/RAB32/RAB38 GEF VARP, and the RAB10 GEFs DENND4A and DENND4C.

    “These included known Retromer accessory proteins, the RAB7 GAP TBC1D546,77–81, the RAB21/RAB32/RAB38 GEF VARP (a.k.a. ANKRD27)47,48,82, and the RAB10 GEFs DENND4A and DENND4C83,84.”

    From Mapping of endosomal proximity proteomes reveals Retromer as a hub for RAB GTPase regulation (2025) · cites this paper as [82]

  • In all cases, the accessory protein directly associates with Retromer through presentation of PL motifs to the same hydrophobic pocket in VPS29 that accommodates PL motifs from TBC1D5, ANKRD27 and the FAM21 subunit of the WASH complex.

    “In all cases, the accessory protein directly associates with Retromer through presentation of PL motifs to the same hydrophobic pocket in VPS29 that accommodates PL motifs from TBC1D5, ANKRD27 and the FAM21 subunit of the WASH complex44,77,82,114.”

    From Mapping of endosomal proximity proteomes reveals Retromer as a hub for RAB GTPase regulation (2025) · cites this paper as [82]

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Metadata

Authors
Crawley-Snowdon, H., Yang, J.-C., Zaccai, N. R., Davis, L. J., Wartosch, L., Herman, E. K., Bright, N. A., Swarbrick, J. S., Collins, B. M., Jackson, L. P., Seaman, M. N. J., Luzio, J. P., Dacks, J. B., Neuhaus, D., & Owen, D. J.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2020-10-06
Volume
11
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-020-18773-2
PMC
PMC7539009
Cited by
35
References
1
Language
en
Licence
Funders
  • Wellcome Trust (090909/Z/09/Z)
  • RCUK | Medical Research Council (MR/R009015/1)
  • RCUK | MRC | Medical Research Foundation (U105178934)
  • Department of Health | National Health and Medical Research Council (APP1136021, APP1156493)
  • U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (R35GM119525)
  • Discovery Grants from the Natural Sciences and Engineering Research Council of Canada

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