Rab geranylgeranyltransferase

Rab geranylgeranyltransferase (RabGGTase; enzyme commission code EC 2.5.1.60) is classified as a transferase enzyme; specifically, it is in the protein prenyltransferase family along with two other enzymes (protein farnesyltransferase and protein geranylgeranyltransferase type-I). The reaction catalyzed by RabGGTase is summarized as follows:

• geranylgeranyl diphosphate + protein-cysteine = S-geranylgeranyl-protein + diphosphate

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 (Chinpaisal).

Rab geranylgeranyltransferase’s “outsourcing” of specificity (using REP to interact with the Rab proteins it prenylates, as mentioned above) 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 (it can prenylate any sequence containing a cysteine residue).

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 (Coxon).

File:Chains and Ions.png

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 (see image to the left) to a resolution of 1.80 Å.{{PDB|3DSS}}; {{cite journal |vauthors=Guo Z, Wu YW, Das D, Delon C, Cramer J, Yu S, Thuns S, Lupilova N, Waldmann H, Brunsveld L, Goody RS, Alexandrov K, Blankenfeldt W | title = Structures of RabGGTase-substrate/product complexes provide insights into the evolution of protein prenylation | journal = EMBO J. | volume = 27 | issue = 18 | pages = 2444–56 |date=September 2008 | pmid = 18756270 | pmc = 2543052 | doi = 10.1038/emboj.2008.164 }} 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 (15 in the alpha subunit and 13 in the beta subunit) and 15 very short (no more than 4 residues) beta sheets. Functional RabGGTase binds three metal ions as ligands: two calcium ions (Ca²⁺) and a zinc ion (Zn²⁺), all of which interact with the beta subunit.

{{Clear}}

• Farnesyltransferase
• Geranylgeranyltransferase type 1 – also referred to as Geranylgeranyltranferase 1 or just Geranylgeranyltranferase
• Prenylation

{{Reflist}}

• Coxon, Fraser P., Frank H. Ebetino, Emilie H. Mules, Miguel C. Seabra, Charles E. McKenna and Michael J. Rogers. Phosphonocarboxylate inhibitors of Rabnext term geranylgeranyl transferase disrupt the prenylation and membrane localization of previous termRabnext term proteins in osteoclasts in vitro and in vivo. Bone Vol. 37, Iss. 3. Sept. 2005, p. 349-358.
• Chinpaisal, Chatchai, Chih-Hao Lee and Li-Na Wei. Studies of the mouse Rabnext term geranylgeranyl transferase β subunit: gene structure, expression and regulation . Gene Vol. 184, Iss. 2 Jan. 1997, p. 237-43.
• {{cite journal | vauthors = Casey PJ, Seabra MC | date = 1996 | title = Protein prenyltransferases | journal = J. Biol. Chem. | volume = 271 | pages = 5289–92 | pmid = 8621375 | doi = 10.1074/jbc.271.10.5289 | issue = 10 | doi-access = free }}
• {{cite journal | vauthors = Wilson AL, Erdman RA, Castellano F, Maltese WA | title = Prenylation of Rab8 GTPase by type I and type II geranylgeranyl transferases | journal = Biochem. J. | volume = 333 | pages = 497–504 | pmid = 9677305 | pmc = 1219609 | issue = Pt 3 | year = 1998 | doi = 10.1042/bj3330497 }}
• {{cite journal | vauthors = Zhang H, Seabra MC, Deisenhofer J | date = 2000 | title = Crystal structure of Rab geranylgeranyltransferase at 2.0 A resolution | journal = Structure. Fold. Des. | volume = 8 | pages = 241–51 | pmid = 10745007 | doi = 10.1016/S0969-2126(00)00102-7 | issue = 3 | doi-access = free }}
• {{cite journal|author1-link=Nicolas H. Thomä | vauthors = Thoma NH, Niculae A, Goody RS, Alexandrov K | date = 2001 | title = Double prenylation by RabGGTase can proceed without dissociation of the mono-prenylated intermediate | journal = J. Biol. Chem. | volume = 276 | pages = 48631–6 | pmid = 11591706 | doi = 10.1074/jbc.M106470200 | issue = 52 | doi-access = free }}
• {{cite journal | author1 = Alexandrov K | date = 2002 | title = In vitro assembly, purification, and crystallization of the rab geranylgeranyl transferase:substrate complex | journal = Protein Expr. Purif. | volume = 25 | pages = 23–30 | pmid = 12071695 | doi = 10.1006/prep.2001.1605 | last2 = Niculae | first2 = A | last3 = Kalinin | first3 = A | last4 = Thomä | first4 = NH | last5 = Sidorovitch | first5 = V | last6 = Goody | first6 = RS | last7 = Alexandrov | first7 = K | issue = 1 }}
• Sinnott, M. (Ed.), Comprehensive Biological Catalysis. A Mechanistic Reference, vol. 1, Academic Press, San Diego, CA, 1998, p. 31-118.

• {{MeshName|Rab+geranylgeranyltransferase}}

{{Alkyl and aryl transferases}}

{{Enzymes}}

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Category:EC 2.5.1