Mechanism and regulation of cargo entry into the Commander endosomal recycling pathway

Rebeka Butkovič (), Alexander P. Walker, Michael D. Healy, Kerrie E. McNally, Meihan Liu, Tineke Veenendaal, Kohji Kato, Nalan Liv, Judith Klumperman, Brett M. Collins () and Peter J. Cullen ()
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Rebeka Butkovič: University of Bristol
Alexander P. Walker: University of Bristol
Michael D. Healy: The University of Queensland
Kerrie E. McNally: University of Bristol
Meihan Liu: The University of Queensland
Tineke Veenendaal: Utrecht University
Kohji Kato: University of Bristol
Nalan Liv: Utrecht University
Judith Klumperman: Utrecht University
Brett M. Collins: The University of Queensland
Peter J. Cullen: University of Bristol

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Commander is a multiprotein complex that orchestrates endosomal recycling of integral cargo proteins and is essential for normal development. While the structure of this complex has recently been described, how cargo proteins are selected for Commander-mediated recycling remains unclear. Here we identify the mechanism through which the unstructured carboxy-terminal tail of the cargo adaptor sorting nexin-17 (SNX17) directly binds to the Retriever sub-complex of Commander. SNX17 adopts an autoinhibited conformation where its carboxy-terminal tail occupies the cargo binding groove. Competitive cargo binding overcomes this autoinhibition, promoting SNX17 endosomal residency and the release of the tail for Retriever association. Furthermore, our study establishes the central importance of SNX17-Retriever association in the handover of integrin and lipoprotein receptor cargoes into pre-existing endosomal retrieval sub-domains. In describing the principal mechanism of cargo entry into the Commander recycling pathway we provide key insight into the function and regulation of this evolutionary conserved sorting pathway.

Date: 2024
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DOI: 10.1038/s41467-024-50971-0

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