Rab geranylgeranyltransferase


Rab geranylgeranyltransferase also known as geranylgeranyltransferase II is one of the three prenyltransferases. It transfers two geranylgeranyl groups to the cystein at the C-terminus of Rab proteins.
The C-terminus of Rab proteins varies in length and sequence and is referred to as hypervariable. Thus Rab proteins do not have a consensus sequence, such as the CAAX box, which the Rab geranylgeranyltransferase can recognise. Instead Rab proteins are bound by the Rab escort protein over a more conserved region of the Rab protein and then presented to the Rab geranylgeranyltransferase.
Once Rab proteins are prenylated, the lipid anchor ensure that Rabs are no longer soluble. REP therefore plays an important role in binding and solubilising the geranylgeranyl groups and delivers the Rab protein to the relevant cell membrane.

Reaction

Rab geranylgeranyltransferase is classified as a transferase enzyme; specifically, it is in the protein prenyltransferase family along with two other enzymes. The reaction catalyzed by RabGGTase is summarized as follows:
This reaction is essential in the control of membrane docking and fusion. Studies of mice have shown that Rab GGTase genes are expressed in all major adult organs, as well as in some embryonic units, including the spinal cord and liver.
Rab geranylgeranyltransferase’s “outsourcing” of specificity is unique among prenyltransferases. Rab GGTase is “responsible for the largest number of individual protein prenylation events in the cell,” probably due to this ability to interact with many different Rab proteins.
In vitro studies have shown that Rab GGTase can be inhibited by nitrogen-containing bisphosphonate drugs such as risedronate; however, the effects of such drugs seem to be much more limited in vivo.

Structure

RabGGTase is a heterodimer composed of alpha and beta subunits that are encoded by the RABGGTA and RABGGTB genes, respectively. The structure of rat RabGGTase has been determined by X-ray diffraction to a resolution of 1.80 Å. RabGGTase’s secondary structure is largely composed of alpha helices; the alpha subunit is 74% helical with no beta sheets, while the beta subunit is 51% helical and 5% beta sheet. There are 28 alpha helices total and 15 very short beta sheets. Functional RabGGTase binds three metal ions as ligands: two calcium ions and a zinc ion, all of which interact with the beta subunit.