GDPdissociation

GDP dissociation inhibitor (GDI) is a regulatory protein that binds to the GDP-bound form of certain small GTPases, notably Rab and ARF family members, and inhibits the release of GDP. By stabilizing the inactive state and controlling localization, GDIs regulate the cycling of these GTPases between membranes and the cytosol, coordinating vesicular trafficking and membrane dynamics.

GDI recognizes prenylated, GDP-bound Rab or ARF proteins and forms a soluble complex. This interaction masks the lipid modification that anchors the GTPase to membranes and prevents GDP dissociation, effectively extracting the GTPase from membranes into the cytosol. Activation occurs when the GTPase is released from GDI and encounters a guanine nucleotide exchange factor (GEF) at a membrane, which promotes GDP-GTP exchange and membrane targeting. In some systems, additional factors such as GDP dissociation factors (GDFs) facilitate release from GDI at the appropriate site.

In humans, two main GDI genes exist: GDI1 and GDI2, encoding Rab GDP-dissociation inhibitors α and β. These proteins bind multiple Rab isoforms, supporting recycling and proper targeting of vesicles. They also regulate Arf family GTPases in a similar fashion, contributing to broader control of vesicle formation and trafficking.

The GDI-mediated reservoir of GDP-bound GTPases ensures tight regulation of membrane trafficking processes, including endocytosis, exocytosis, and organelle biogenesis. Disruption of GDI function or Rab/Arf cycling has been associated with neurodevelopmental and neurodegenerative disorders and with certain cancers, reflecting the central role of GDI in cellular logistics.