Identification of a GDI displacement factor that releases endosomal Rab GTPases from Rab-GDI

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Abstract
Prenylated Rab GTPases occur in the cytosol in their GDP‐bound conformations bound to a cytosolic protein termed GDP‐dissociation inhibitor (GDI). Rab–GDI complexes represent a pool of active, recycling Rab proteins that can deliver Rabs to specific and distinct membrane‐bound compartments. Rab delivery to cellular membranes involves release of GDI, and the membrane‐associated Rab protein then exchanges its bound GDP for GTP. We report here the identification of a novel, membrane‐associated protein factor that can release prenylated Rab proteins from GDI. This GDI‐displacement factor (GDF) is not a guanine nucleotide exchange factor because it did not influence the intrinsic rates of nucleotide exchange by Rabs 5, 7 or 9. Rather, GDF caused the release of each of these endosomal Rabs from GDI, permitting them to exchange nucleotide at their intrinsic rates. GDF displayed the greatest catalytic rate enhancement on Rab9–GDI complexes. However, catalytic rate enhancement paralleled the potency of GDI in blocking nucleotide exchange: GDI was shown to be most potent in blocking nucleotide exchange by Rab9. The failure of GDF to act on Rab1–GDI complexes suggests that it may be specific for endosomal Rab proteins. This novel, membrane‐associated activity may be part of the machinery used to localize Rabs to their correct intracellular compartments.