Structural basis for Rab6 activation by the Ric1-Rgp1 complex

J. Ryan Feathers, Ryan C. Vignogna and J. Christopher Fromme ()
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J. Ryan Feathers: Cornell University
Ryan C. Vignogna: Cornell University
J. Christopher Fromme: Cornell University

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract Rab GTPases act as molecular switches to regulate organelle homeostasis and membrane trafficking. Rab6 plays a central role in regulating cargo flux through the Golgi and is activated via nucleotide exchange by the Ric1-Rgp1 protein complex. Ric1-Rgp1 is conserved throughout eukaryotes but the structural and mechanistic basis for its function has not been established. Here we report the cryoEM structure of a Ric1-Rgp1‐Rab6 complex representing a key intermediate of the nucleotide exchange reaction. Ric1-Rgp1 interacts with the nucleotide-binding domain of Rab6 using an uncharacterized helical domain, which we establish as a RabGEF domain by identifying residues required for Rab6 activation. Unexpectedly, the complex uses an arrestin fold to interact with the Rab6 hypervariable domain, indicating that interactions with the unstructured C-terminal regions of Rab GTPases may be a common binding mechanism used by their activators. Collectively, our findings provide a detailed mechanistic understanding of regulated Rab6 activation at the Golgi.

Date: 2024
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DOI: 10.1038/s41467-024-54869-9

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