GDIs

GDP-dissociation inhibitors, or GDIs, are a family of regulatory proteins that control the activity and localization of small GTPases in eukaryotic cells. The term covers proteins that bind to GDP-bound forms of GTPases in the Ras superfamily, including Rho, Rab, and Ran subfamilies, thereby modulating their cycling between inactive and active states.

Mechanistically, GDIs bind to prenylated GTPases and shield the hydrophobic lipid tail, keeping the proteins soluble in the cytosol and preventing spontaneous activation. By stabilizing the GDP-bound form, GDIs slow or block nucleotide exchange. They can also influence the localization of GTPases by extracting them from membranes and cycling them between membrane-bound and cytosolic pools, coordinating signaling and trafficking processes.

Subtypes and nomenclature commonly reflect the GTPase family they regulate. RhoGDI binds Rho family members, RabGDI targets Rab GTPases involved in vesicle trafficking, and RanGDI interacts with Ran in nucleocytoplasmic transport. In humans, genes such as GDI1, GDI2, and GDI3 encode various GDIs with tissue-specific expression and functions. While the best-characterized roles relate to Rho and Rab signaling pathways, GDIs collectively serve as chaperones that maintain proper GTPase localization and availability for activation by guanine nucleotide exchange factors (GEFs).

Biological significance and disease associations vary by context, but GDIs are generally important for development, neuronal function, and membrane trafficking. Dysregulation of GDI activity can disrupt signaling networks, cytoskeletal dynamics, and vesicle transport, contributing to disease processes such as cancer and neurodegenerative disorders.