Organization of the Rab‐GDI/CHM Superfamily: The Functional Basis for Choroideremia Disease

Abstract

Choroideremia is an X-chromosome-linked disease that leads to the degeneration of the choriocapillaris, the retinal pigment epithelium and the photoreceptor layer in the eye. The gene product defective in choroideremia, CHM, is identical to Rab escort protein 1 (REP1). CHM/ REP1 is an essential component of the catalytic geranylgeranyltransferase II complex (GGTrII) that delivers newly synthesized small GTPases belonging to the RAB gene family to the catalytic complex for post-translational modification. CHM/REP family members are evolutionarily related to members of the guanine nucleotide dissociation inhibitor (GDI) family, proteins involved in the recycling of Rab proteins required for vesicular membrane trafficking through the exocytic and endocytic pathways, forming the GDI/CHM superfamily. Biochemical and structural analyses have now revealed a striking parallel in the organization and function of these two families allowing us to generate a general model for GDI/CHM superfamily function in health and disease.

Male NOD mouse external lacrimal glands exhibit profound changes in the exocytotic pathway early in postnatal development

“…Rab3D, like other rab proteins, exists in GTP and GDP bound forms with the cycling between these forms modulated by other proteins including GDP dissociation inhibitors and membrane receptors. Changes in rab3D function independent of altered protein expression could be elicited in a variety of ways including altered prenylation through CHM/Rep (Alory and Balch, 2001), phosphorylation by rab3D kinase (Pombo et al, 2001) or altered expression of effectors that modulate its activity such as GDP dissociation inhibitors or GTPase activators (Wu et al, 1996). General changes in the signaling environment could also be responsible for altered functioning of rab3D and other effectors of the exocytotic pathway.…”

Protein LidA from Legionella is a Rab GTPase supereffector

“…Second, at later stages of infection, Rab1 disappears from the LCV (23). This process requires Rab1 to return to the GDP-bound state, because only inactive but not active Rabs can interact with and be extracted by the protein GDP dissociation inhibitor (GDI) (24)(25)(26). To return Rab1∶GTP to the GDP state, the Rab1-GAPs LepB (from Legionella) (23) or the human GAP TBC1D20 (27) needs to access Rab1 and stimulate GTP hydrolysis.…”

A Structural Model of the GDP Dissociation Inhibitor Rab Membrane Extraction Mechanism

“…1A), whereas the apo-form of bovine ␣-GDI shows a closed lipid binding pocket (7). Since have we studied the yeast Rab membrane extraction/delivery system, we have now solved the crystal structure of yeast apo-GDI, which exhibits ϳ50% amino acid sequence identity to the bovine equivalent.…”

“…differences (from blue for 0 -0.2 Å to red for 3.5-3.8 Å) between C␣ coordinates of apo-GDI and GTPase-bound GDI. Secondary structure elements are labeled according to the bovine GDI structure (7). C, superimposition of apo-GDI and Ypt1-bound GDI domain II.…”

“…GDI does not facilitate Rab prenylation but serves as a generic regulator for recycling of Rab-GTPases (6) for use in multiple rounds of membrane transport. It retrieves Rab in the GDPbound form from the membrane and delivers it to the cytosol, controlling the distribution of Rabs between membranes and cytosol (7). GDI is believed to be stably associated only with GDP-loaded and prenylated Rab/Ypt proteins, ensuring retrieval of inactivated GTPases from the membrane at the end of their functional cycle (8).…”