RabGDI

Rab GDP-dissociation inhibitor, commonly abbreviated RabGDI, is a soluble cytosolic protein that regulates Rab GTPases, the master switches of vesicular trafficking in eukaryotic cells. RabGDI binds Rab proteins in their GDP-bound, inactive state and shields their C-terminal geranylgeranyl lipid modifications, preventing premature membrane association. By solubilizing Rabs, RabGDI maintains a readily available cytosolic Rab pool for rapid redeployment to membranes.

In the Rab cycle, RabGDI extracts Rab-GDP from membranes and delivers it to other membranes where guanine nucleotide exchange factors (GEFs) promote GDP-to-GTP exchange and Rab activation. Once Rab is GTP-bound, it dissociates from RabGDI and engages effectors to drive vesicle budding, movement, and fusion. GTP hydrolysis by GTPase-activating proteins (GAPs) returns Rab to the GDP-bound state, allowing RabGDI to rebind and solubilize it again for recycling.

Two mammalian paralogs exist: GDI1 (RabGDI α) and GDI2 (RabGDI β). GDI1 is enriched in neurons, while GDI2 shows broader expression. They share substantial sequence similarity and perform overlapping but not completely redundant roles across multiple trafficking routes, including endosomal and Golgi–ER pathways.

Structureally, RabGDI presents a hydrophobic pocket that accommodates Rab’s geranylgeranyl group, enabling stable RabGDI–Rab-GDP complex formation. This chaperone-like activity prevents Rab aggregation in the cytosol and coordinates Rab recycling with GEFs, GAPs, and membrane targeting.

Clinically, RabGDI function is essential for normal vesicle trafficking, and dysregulation has been examined in experimental models of neurological disorders, reflecting its importance in neuronal and cellular homeostasis. Further research continues to clarify its roles across tissues and diseases.