Thematic review series: Lipid Posttranslational Modifications. Structural biology of protein farnesyltransferase and geranylgeranyltransferase type I
2006; Elsevier BV; Volume: 47; Issue: 4 Linguagem: Inglês
10.1194/jlr.r600002-jlr200
ISSN1539-7262
Autores Tópico(s)Biotin and Related Studies
ResumoMore than 100 proteins necessary for eukaryotic cell growth, differentiation, and morphology require posttranslational modification by the covalent attachment of an isoprenoid lipid (prenylation). Prenylated proteins include members of the Ras, Rab, and Rho families, lamins, CENPE and CENPF, and the γ subunit of many small heterotrimeric G proteins. This modification is catalyzed by the protein prenyltransferases: protein farnesyltransferase (FTase), protein geranylgeranyltransferase type I (GGTase-I), and GGTase-II (or RabGGTase). In this review, we examine the structural biology of FTase and GGTase-I (the CaaX prenyltransferases) to establish a framework for understanding the molecular basis of substrate specificity and mechanism. These enzymes have been identified in a number of species, including mammals, fungi, plants, and protists. Prenyltransferase structures include complexes that represent the major steps along the reaction path, as well as a number of complexes with clinically relevant inhibitors. Such complexes may assist in the design of inhibitors that could lead to treatments for cancer, viral infection, and a number of deadly parasitic diseases. More than 100 proteins necessary for eukaryotic cell growth, differentiation, and morphology require posttranslational modification by the covalent attachment of an isoprenoid lipid (prenylation). Prenylated proteins include members of the Ras, Rab, and Rho families, lamins, CENPE and CENPF, and the γ subunit of many small heterotrimeric G proteins. This modification is catalyzed by the protein prenyltransferases: protein farnesyltransferase (FTase), protein geranylgeranyltransferase type I (GGTase-I), and GGTase-II (or RabGGTase). In this review, we examine the structural biology of FTase and GGTase-I (the CaaX prenyltransferases) to establish a framework for understanding the molecular basis of substrate specificity and mechanism. These enzymes have been identified in a number of species, including mammals, fungi, plants, and protists. Prenyltransferase structures include complexes that represent the major steps along the reaction path, as well as a number of complexes with clinically relevant inhibitors. Such complexes may assist in the design of inhibitors that could lead to treatments for cancer, viral infection, and a number of deadly parasitic diseases. More than 100 proteins necessary for eukaryotic cell growth, differentiation, and morphology require posttranslational modification by the covalent attachment of an isoprenoid lipid (prenylation) (1Tamanoi F. Sigman D.S. The Enzymes. Academic Press, San Diego, CA2001Google Scholar). This modification is catalyzed by three protein prenyltransferases: protein farnesyltransferase (FTase) and protein geranylgeranyltransferase type I (GGTase-I), collectively termed the CaaX prenyltransferases, as well as protein GGTase-II (or RabGGTase) [reviewed in this series in (2Leung K.F. Baron R. Seabra M.C. Geranylgeranylation of Rab GTPases.J. Lipid Res. 2006; 47: 467-475Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar)], whose substrates are limited to members of the Rab subfamily of G proteins. FTase and GGTase-I transfer a 15 or 20 carbon isoprenoid [donated by farnesyl diphosphate (FPP) or geranylgeranyl diphosphate (GGPP)], respectively, to the cysteine of a C-terminal CaaX motif, defined by a cysteine (C) residue, followed by two small, generally aliphatic (a) residues, and the X residue, which contributes significantly to specificity (Fig. 1) (1Tamanoi F. Sigman D.S. The Enzymes. Academic Press, San Diego, CA2001Google Scholar, 2Leung K.F. Baron R. Seabra M.C. Geranylgeranylation of Rab GTPases.J. Lipid Res. 2006; 47: 467-475Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 3Reiss Y. Goldstein J.L. Seabra M.C. Casey P.J. Brown M.S. Inhibition of purified p21ras farnesyl:protein transferase by Cys-AAX tetrapeptides.Cell. 1990; 62: 81-88Abstract Full Text PDF PubMed Scopus (687) Google Scholar, 4Goldstein J.L. Brown M.S. Stradley S.J. Reiss Y. Geirasch L.M. Nonfarnesylated tetrapeptide inhibitors of protein farnesyltransferase.J. Biol. Chem. 1991; 266: 15575-15578Abstract Full Text PDF PubMed Google Scholar, 5Moores S.L. Schaber M.D. Mosser S.D. Rands E. O'Hara M.B. Garsky V.M. Marshall M.S. Pompliano D.L. Gibbs J.B. Sequence dependence of protein isoprenylation.J. Biol. Chem. 1991; 266: 14603-14610Abstract Full Text PDF PubMed Google Scholar, 6Reiss Y. Stradley S.J. Gierasch L.M. Brown M.S. Goldstein J.L. Sequence requirements for peptide recognition by rat brain p21ras farnesyl:protein transferase.Proc. Natl. Acad. Sci. USA. 1991; 88: 732-736Crossref PubMed Google Scholar, 7Brown M.S. Goldstein J.L. Paris K.J. Burnier J.P. Marsters J.C. Tetrapeptide inhibitors of protein farnesyltransferase: amino-terminal substitution in phenylalanine-containing tetrapeptides restores farnesylation.Proc. Natl. Acad. Sci. USA. 1992; 89: 8313-8316Crossref PubMed Google Scholar, 8Pompliano D.L. Rands E. Schaber M.D. Mosser S.D. Anthony N.J. Gibbs J.B. Steady-state kinetic mechanism of ras farnesyl:protein transferase.Biochemistry. 1992; 31: 3800-3807Crossref PubMed Scopus (244) Google Scholar, 9Caplin B.E. Hettich L.A. Marshall M.S. Substrate characterization of the Saccharomyces cerevisiae protein farnesyltransferase and type-I protein geranylgeranyltransferase.Biochim. Biophys. Acta. 1994; 1205: 39-48Crossref PubMed Scopus (0) Google Scholar). Kinetic assays and analysis of lipidated CaaX proteins purified from the cell demonstrate the general preference of FTase for methionine, serine, glutamine, or alanine and the preference of GGTase-I for leucine or phenylalanine in the X position. Here, we review the structural biology of FTase and GGTase-I; the biochemical properties of these enzymes have been reviewed extensively elsewhere (1Tamanoi F. Sigman D.S. The Enzymes. Academic Press, San Diego, CA2001Google Scholar, 10Casey P.J. Biochemistry of protein prenylation.J. Lipid Res. 1992; 33: 1731-1740Abstract Full Text PDF PubMed Google Scholar, 11Casey P.J. Protein lipidation in cell signaling.Science. 1995; 268: 221-225Crossref PubMed Google Scholar, 12Casey P.J. Seabra M.C. Protein prenyltransferases.J. Biol. Chem. 1996; 271: 5289-5292Abstract Full Text Full Text PDF PubMed Scopus (661) Google Scholar, 13Zhang F.L. Casey P.J. Protein prenylation: molecular mechanisms and functional consequences.Annu. Rev. Biochem. 1996; 65: 241-269Crossref PubMed Google Scholar, 14Fu H.W. Casey P.J. Enzymology and biology of CaaX protein prenylation.Recent Prog. Horm. Res. 1999; 54: 315-342PubMed Google Scholar, 15Winter-Vann A.M. Casey P.J. Post-prenylation-processing enzymes as new targets in oncogenesis.Nat. Rev. Cancer. 2005; 5: 405-412Crossref PubMed Scopus (256) Google Scholar). After covalent attachment of the isoprenoid in the cytoplasm, most CaaX proteins undergo two further prenylation-dependent processing steps at the endoplasmic reticulum (1Tamanoi F. Sigman D.S. The Enzymes. Academic Press, San Diego, CA2001Google Scholar): proteolytic removal of the aaX tripeptide by the CaaX protease Ras and a-factor-converting enzyme (Rce1), and carboxymethylation of the prenylcysteine residue by the enzyme Isoprenylcysteine carboxyl methyltransferase (Icmt). The fully processed proteins exhibit high affinity for cellular membranes and present a unique structure at their C termini that can serve as a specific recognition motif in certain protein-protein interactions (Fig. 2). FTase and GGTase-I were first identified in 1990 and 1991, respectively (3Reiss Y. Goldstein J.L. Seabra M.C. Casey P.J. Brown M.S. Inhibition of purified p21ras farnesyl:protein transferase by Cys-AAX tetrapeptides.Cell. 1990; 62: 81-88Abstract Full Text PDF PubMed Scopus (687) Google Scholar, 16Seabra M.C. Reiss Y. Casey P.J. Brown M.S. Goldstein J.L. Protein farnesyltransferase and geranylgeranyltransferase share a common alpha subunit.Cell. 1991; 65: 429-434Abstract Full Text PDF PubMed Scopus (293) Google Scholar). Both enzymes have been identified in a number of species, including mammals (17Reiss Y. Seabra M.C. Armstrong S.A. Slaughter C.A. Goldstein J.L. Brown M.S. Nonidentical subunits of p21 H-ras farnesyltransferase: peptide binding and farnesyl pyrophosphate carrier functions.J. Biol. Chem. 1991; 266: 10672-10677Abstract Full Text PDF PubMed Google Scholar, 18Yokoyama K. Goodwin G.W. Ghomashchi F. Glomset J.A. Gelb M.H. A protein geranylgeranyltransferase from bovine brain: implications for protein prenylation specificity.Proc. Natl. Acad. Sci. USA. 1991; 88: 5302-5306Crossref PubMed Scopus (0) Google Scholar, 19Moomaw J.F. Casey P.J. Mammalian protein geranylgeranyltransferase: subunit composition and metal requirements.J. Biol. Chem. 1992; 267: 17438-17443Abstract Full Text PDF PubMed Google Scholar, 20Omer C.A. Kral A.M. Diehl R.E. Prendergast G.C. Powers S. Allen C.M. Gibbs J.B. Kohl N.E. Characterization of recombinant human farnesyl-protein transferase: cloning, expression, farnesyl diphosphate binding, and functional homology with yeast prenyl-protein transferases.Biochemistry. 1993; 32: 5167-5176Crossref PubMed Scopus (0) Google Scholar, 21Yokoyama K. Gelb M.H. Purification of a mammalian protein geranylgeranyltransferase: formation and catalytic properties of an enzyme-geranylgeranyl diphosphate complex.J. Biol. Chem. 1993; 268: 4055-4060Abstract Full Text PDF PubMed Google Scholar), fungi (22He B. Chen P. Vancura K.L. Michaelis S. Powers S. RAM2, an essential gene in yeast, and RAM1 encode the two polypeptide components of the farnesyltransferase that prenylates a-factor and ras proteins.Proc. Natl. Acad. Sci. USA. 1991; 88: 11373-11377Crossref PubMed Scopus (0) Google Scholar, 23Mayer M.L. Caplin B.E. Marshall M.S. CDC43 and RAM2 encode the polypeptide subunits of a yeast type I protein geranylgeranyltransferase.J. Biol. Chem. 1992; 267: 20589-20593Abstract Full Text PDF PubMed Google Scholar, 24Kelly R. Card D. Register E. Mazur P. Kelly T. Tanaka K.I. Onishi J. Williamson J.M. Fan H. Satoh T. et al.Geranylgeranyltransferase I of Candida albicans: null mutants or enzyme inhibitors produce unexpected phenotypes.J. Bacteriol. 2000; 182: 704-713Crossref PubMed Scopus (0) Google Scholar, 25Vallim M.A. Fernandes L. Alspaugh J.A. The RAM1 gene encoding a protein-farnesyltransferase β-subunit homologue is essential in Cryptococcus neoformans.Microbiology. 2004; 150: 1925-1935Crossref PubMed Scopus (38) Google Scholar), plants (26Qian D. Zhou D. Ju R. Cramer C.L. Yang Z. Protein farnesyltransferase in plants: molecular characterization and involvement in cell cycle control.Plant Cell. 1996; 8: 2381-2394PubMed Google Scholar, 27Caldelari D. Sternberg H. Rodriguez-Concepcion M. Gruissem W. Yalovsky S. Efficient prenylation by a plant geranylgeranyltransferase-I requires a functional CaaL box motif and a proximal polybasic domain.Plant Physiol. 2001; 126: 1416-1429Crossref PubMed Scopus (0) Google Scholar), and protists (28Yokoyama K. Trobridge P. Buckner F.S. Van Voorhis W.C. Stuart K.D. Gelb M.H. Protein farnesyltransferase from Trypanosoma brucei. A heterodimer of 61- and 65-kDa subunits as a new target for antiparasite therapeutics.J. Biol. Chem. 1998; 273: 26497-26505Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 29Chakrabarti D. Azam T. DelVecchio C. Qiu L. Park Y.I. Allen C.M. Protein prenyl transferase activities of Plasmodium falciparum.Mol. Biochem. Parasitol. 1998; 94: 175-184Crossref PubMed Scopus (105) Google Scholar); the genes encoding FTase and GGTase-I have been cloned from several of these species (20Omer C.A. Kral A.M. Diehl R.E. Prendergast G.C. Powers S. Allen C.M. Gibbs J.B. Kohl N.E. Characterization of recombinant human farnesyl-protein transferase: cloning, expression, farnesyl diphosphate binding, and functional homology with yeast prenyl-protein transferases.Biochemistry. 1993; 32: 5167-5176Crossref PubMed Scopus (0) Google Scholar, 30Chen W-J. Andres D.A. Goldstein J.L. Brown M.S. Cloning and expression of a cDNA encoding the alpha subunit of rat p21ras protein farnesyltransferase.Proc. Natl. Acad. Sci. USA. 1991; 88: 11368-11372Crossref PubMed Google Scholar, 31Chen W-J. Andres D.A. Goldstein J.L. Russell D.W. Brown M.S. cDNA cloning and expression of the peptide binding beta subunit of rat p21ras farnesyltransferase, the counterpart of yeast RAM1/DPR1.Cell. 1991; 66: 327-334Abstract Full Text PDF PubMed Google Scholar, 32Zhang F.L. Diehl R.E. Kohl N.E. Gibbs J.B. Giros B. Casey P.J. Omer C.A. cDNA cloning and expression of rat and human protein geranylgeranyltransferase type-I.J. Biol. Chem. 1994; 269: 3175-3180Abstract Full Text PDF PubMed Google Scholar, 33Zhang F.L. Mammalian protein geranylgeranyltransferase type I: cloning, expression and enzymatic studies. PhD Dissertation. Duke University, Durham, NC1995Google Scholar, 34Buckner F.S. Yokoyama K. Nguyen L. Grewal A. Erdjument-Bromage H. Tempst P. Strickland C.L. Xiao L. Van Voorhis W.C. Gelb M.H. Cloning, heterologous expression, and distinct substrate specificity of protein farnesyltransferase from Trypanosoma brucei.J. Biol. Chem. 2000; 275: 21870-21876Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 35Buckner F.S. Eastman R.T. Nepomuceno-Silva J.L. Speelmon E.C. Myler P.J. Van Voorhis W.C. Yokoyama K. Cloning, heterologous expression, and substrate specificities of protein farnesyltransferases from Trypanosoma cruzi and Leishmania major.Mol. Biochem. Parasitol. 2002; 122: 181-188Crossref PubMed Scopus (45) Google Scholar). These enzymes have been shown to be essential for the function of these organisms: elimination of these enzymes results in severe defects or lethality in many instances (22He B. Chen P. Vancura K.L. Michaelis S. Powers S. RAM2, an essential gene in yeast, and RAM1 encode the two polypeptide components of the farnesyltransferase that prenylates a-factor and ras proteins.Proc. Natl. Acad. Sci. USA. 1991; 88: 11373-11377Crossref PubMed Scopus (0) Google Scholar, 26Qian D. Zhou D. Ju R. Cramer C.L. Yang Z. Protein farnesyltransferase in plants: molecular characterization and involvement in cell cycle control.Plant Cell. 1996; 8: 2381-2394PubMed Google Scholar, 36Goodman L.E. Judd S.R. Farnsworth C.C. Powers S. Gelb M.H. Glomset J.A. Tamanoi F. Mutants of Saccharomyces cerevisiae defective in the farnesylation of Ras proteins.Proc. Natl. Acad. Sci. USA. 1990; 87: 9665-9669Crossref PubMed Google Scholar, 37Johnson D.I. Pringle J.R. Molecular characterization of CDC42, a Saccharomyces cerevisiae gene involved in the development of cell polarity.J. Cell Biol. 1990; 111: 143-152Crossref PubMed Scopus (395) Google Scholar, 38Johnson C.D. Chary S.N. Chernoff E.A. Zeng Q. Running M.P. Crowell D.N. Protein geranylgeranyltransferase I is involved in specific aspects of abscisic acid and auxin signaling in Arabidopsis.Plant Physiol. 2005; 139: 722-733Crossref PubMed Scopus (55) Google Scholar). Since the initial discovery of farnesylated fungal proteins, many more proteins have been demonstrated to contain a prenyl modification, including >100 human proteins. These include members of the Ras (39Der C.J. Cox A.D. Isoprenoid modification and plasma membrane association: critical factors for ras oncogenicity.Cancer Cells. 1991; 3: 331-340PubMed Google Scholar, 40Carboni J.M. Yan N. Cox A.D. Bustelo X. Graham S.M. Lynch M.J. Weinmann R. Seizinger B.R. Der C.J. Barbacid M. et al.Farnesyltransferase inhibitors are inhibitors of Ras, but not R-Ras2/TC21, transformation.Oncogene. 1995; 10: 1905-1913PubMed Google Scholar, 41Ellis C.A. Vos M.D. Howell H. Vallecorsa T. Fults D.W. Clark G.J. Rig is a novel Ras-related protein and potential neural tumor suppressor.Proc. Natl. Acad. Sci. USA. 2002; 99: 9876-9881Crossref PubMed Scopus (46) Google Scholar, 42Kontani K. Tada M. Ogawa T. Okai T. Saito K. Araki Y. Katada T. Di-Ras, a distinct subgroup of ras family GTPases with unique biochemical properties.J. Biol. Chem. 2002; 277: 41070-41078Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar), Rho (43Yamane H.K. Farnsworth C.C. Xie H.Y. Evans T. Howald W.N. Gelb M.H. Glomset J.A. Clarke S. Fung B.K. Membrane-binding domain of the small G protein G25K contains an S-(all-trans-geranylgeranyl)cysteine methyl ester at its carboxyl terminus.Proc. Natl. Acad. Sci. USA. 1991; 88: 286-290Crossref PubMed Google Scholar, 44Yoshida Y. Kawata M. Katayama M. Horiuchi H. Kita Y. Takai Y. A geranylgeranyltransferase for rhoA p21 distinct from the farnesyltransferase for ras p21S.Biochem. Biophys. Res. Commun. 1991; 175: 720-728Crossref PubMed Google Scholar, 45Adamson P. Marshall C.J. Hall A. Tilbrook P.A. Post-translation modifications of p21rho proteins.J. Biol. Chem. 1992; 267: 20033-20038Abstract Full Text PDF PubMed Google Scholar, 46Nobes C.D. Lauritzen I. Mattei M.G. Paris S. Hall A. Chardin P. A new member of the Rho family, Rnd1, promotes disassembly of actin filament structures and loss of cell adhesion.J. Cell Biol. 1998; 141: 187-197Crossref PubMed Scopus (295) Google Scholar, 47Hoffman G.R. Nassar N. Cerione R.A. Structure of the Rho family GTP-binding protein Cdc42 in complex with the multifunctional regulator RhoGDI.Cell. 2000; 100: 345-356Abstract Full Text Full Text PDF PubMed Google Scholar), Rac (48Kinsella B.T. Erdman R.A. Maltese W.A. Carboxyl-terminal isoprenylation of ras-related GTP-binding proteins encoded by rac1, rac2, and ralA.J. Biol. Chem. 1991; 266: 9786-9794Abstract Full Text PDF PubMed Google Scholar), Rap (49Buss J.E. Quilliam L.A. Kato K. Casey P.J. Solski P.A. Wong G. Clark R. McCormick F. Bokoch G.M. Der C.J. The COOH-terminal domain of the Rap1A (Krev-1) protein is isoprenylated and supports transformation by an H-Ras:Rap1A chimeric protein.Mol. Cell. Biol. 1991; 11: 1523-1530Crossref PubMed Scopus (0) Google Scholar, 50Farrell F.X. Yamamoto K. Lapetina E.G. Prenyl group identification of rap2 proteins: a ras superfamily member other than ras that is farnesylated.Biochem. J. 1993; 289: 349-355Crossref PubMed Google Scholar), and Rab (51Kinsella B.T. Maltese W.A. rab GTP-binding proteins with three different carboxyl-terminal cysteine motifs are modified in vivo by 20-carbon isoprenoids.J. Biol. Chem. 1992; 267: 3940-3945Abstract Full Text PDF PubMed Google Scholar, 52Farnsworth C.C. Seabra M.C. Ericsson L.H. Gelb M.H. Glomset J.A. Rab geranylgeranyl transferase catalyzes the geranylgeranylation of adjacent cysteines in the small GTPases, Rab1A, Rab3A and Rab5A.Proc. Natl. Acad. Sci. USA. 1994; 91: 11963-11967Crossref PubMed Scopus (0) Google Scholar) families, the γ subunit of heterotrimeric G proteins (53Lai R.K. Perez-Sala D. Canada F.J. Rando R.R. The gamma subunit of transducin is farnesylated.Proc. Natl. Acad. Sci. USA. 1990; 87: 7673-7677Crossref PubMed Google Scholar, 54Ray K. Kunsch C. Bonner L.M. Robishaw J.D. Isolation of cDNA clones encoding eight different human G protein γ subunits, including three novel forms designated the γ 4, γ 10, and γ 11 subunits.J. Biol. Chem. 1995; 270: 21765-21771Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar), centromeric proteins (55Ashar H.R. James L. Gray K. Carr D. Black S. Armstrong L. Bishop W.R. Kirschmeier P. Farnesyl transferase inhibitors block the farnesylation of CENP-E and CENP-F and alter the association of CENP-E with the microtubules.J. Biol. Chem. 2000; 275: 30451-30457Abstract Full Text Full Text PDF PubMed Scopus (298) Google Scholar), and many other proteins involved in a variety of cell signaling pathways controlling the cell cycle and apoptosis (56Jefferson A.B. Majerus P.W. Properties of type II inositol polyphosphate 5-phosphatase.J. Biol. Chem. 1995; 270: 9370-9377Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 57De Smedt F. Boom A. Pesesse X. Schiffmann S.N. Erneux C. Post-translational modification of human brain type I inositol-1,4,5-trisphosphate 5-phosphatase by farnesylation.J. Biol. Chem. 1996; 271: 10419-10424Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar) as well as glycogen metabolism (58Heilmeyer Jr., L.M. Serwe M. Weber C. Metzger J. Hoffmann-Posorske E. Meyer H.E. Farnesylcysteine, a constituent of the alpha and beta subunits of rabbit skeletal muscle phosphorylase kinase: localization by conversion to S-ethylcysteine and by tandem mass spectrometry.Proc. Natl. Acad. Sci. USA. 1992; 89: 9554-9558Crossref PubMed Scopus (0) Google Scholar), cellular framework (59Farnsworth C.C. Wolda S.L. Gelb M.H. Glomset J.A. Human lamin B contains a farnesylated cysteine residue.J. Biol. Chem. 1989; 264: 20422-20429Abstract Full Text PDF PubMed Google Scholar, 60Lutz R.J. Trujillo M.A. Denham K.S. Wenger L. Sinensky M. Nucleoplasmic localization of prelamin A: implications for prenylation-dependent lamin A assembly into the nuclear lamina.Proc. Natl. Acad. Sci. USA. 1992; 89: 3000-3004Crossref PubMed Google Scholar, 61Kutzleb C. Sanders G. Yamamoto R. Wang X. Lichte B. Petrasch-Parwez E. Kilimann M.W. Paralemmin, a prenyl-palmitoyl-anchored phosphoprotein abundant in neurons and implicated in plasma membrane dynamics and cell process formation.J. Cell Biol. 1998; 143: 795-813Crossref PubMed Scopus (58) Google Scholar), and visual signal transduction (53Lai R.K. Perez-Sala D. Canada F.J. Rando R.R. The gamma subunit of transducin is farnesylated.Proc. Natl. Acad. Sci. USA. 1990; 87: 7673-7677Crossref PubMed Google Scholar, 62Anant J.S. Ong O.C. Xie H. Clarke S. O'Brien P.J. Fung B. K-K. In vivo differential prenylation of retinal cyclic GMP phosphodiesterase catalytic subunits.J. Biol. Chem. 1992; 267: 687-690Abstract Full Text PDF PubMed Google Scholar, 63Inglese J. Koch W.J. Caron M.G. Lefkowitz R.J. Isoprenylation in regulation of signal transduction by G-protein-coupled receptor kinases.Nature. 1992; 359: 147-150Crossref PubMed Scopus (222) Google Scholar, 64Weiss E.R. Ducceschi M.H. Horner T.J. Li A. Craft C.M. Osawa S. Species-specific differences in expression of G-protein-coupled receptor kinase (GRK) 7 and GRK1 in mammalian cone photoreceptor cells: implications for cone cell phototransduction.J. Neurosci. 2001; 21: 9175-9184Crossref PubMed Google Scholar). Defects in these proteins are associated with a number of human diseases, including Batten disease (65Phillips S.N. Benedict J.W. Weimer J.M. Pearce D.A. CLN3, the protein associated with Batten disease: structure, function and localization.J. Neurosci. Res. 2005; 79: 573-583Crossref PubMed Scopus (92) Google Scholar), autosomal recessive retinitis pigmentosa and autosomal dominant retinitis pigmentosa (66McLaughlin M.E. Sandberg M.A. Berson E.L. Dryja T.P. Recessive mutations in the gene encoding the beta-subunit of rod phosphodiesterase in patients with retinitis pigmentosa.Nat. Genet. 1993; 4: 130-134Crossref PubMed Scopus (470) Google Scholar, 67McLaughlin M.E. Ehrhart T.L. Berson E.L. Dryja T.P. Mutation spectrum of the gene encoding the beta subunit of rod phosphodiesterase among patients with autosomal recessive retinitis pigmentosa.Proc. Natl. Acad. Sci. USA. 1995; 92: 3249-3253Crossref PubMed Google Scholar, 68Yamamoto S. Khani S.C. Berson E.L. Dryja T.P. Evaluation of the rhodopsin kinase gene in patients with retinitis pigmentosa.Exp. Eye Res. 1997; 65: 249-253Crossref PubMed Scopus (0) Google Scholar), Canavan disease (69Surendran S. Matalon K.M. Tyring S.K. Matalon R. Molecular basis of Canavan's disease: from human to mouse.J. Child Neurol. 2003; 18: 604-610Crossref PubMed Google Scholar), Emery-Dreifuss muscular dystrophy type 2 (70Nagano A. Arahata K. Nuclear envelope proteins and associated diseases.Curr. Opin. Neurol. 2000; 13: 533-539Crossref PubMed Scopus (0) Google Scholar, 71Pendas A.M. Zhou Z. Cadinanos J. Freije J.M. Wang J. Hultenby K. Astudillo A. Wernerson A. Rodriguez F. Tryggvason K. et al.Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase-deficient mice.Nat. Genet. 2002; 31: 94-99Crossref PubMed Scopus (388) Google Scholar, 72Gruenbaum Y. Goldman R.D. Meyuhas R. Mills E. Margalit A. Fridkin A. Dayani Y. Prokocimer M. Enosh A. The nuclear lamina and its functions in the nucleus.Int. Rev. Cytol. 2003; 226: 1-62Crossref PubMed Scopus (180) Google Scholar), and a variety of human cancers. Some of the most studied CaaX proteins are members of the Ras family, mutations in which occur in ∼20–30% of all human tumors, making the CaaX prenyltransferases targets for inhibition in cancer therapeutics (73Barbacid M. ras genes.Annu. Rev. Biochem. 1987; 56: 779-827Crossref PubMed Google Scholar, 74Oliff A. Farnesyltransferase inhibitors: targeting the molecular basis of cancer.Biochim. Biophys. Acta. 1999; 1423: C19-C30PubMed Google Scholar) (see below). Over the past decade, high-resolution crystal structures of FTase and GGTase-I complexed with various substrates, products, and inhibitors have advanced our understanding of these enzymes. Structures representing each of the major steps along the reaction pathway of CaaX prenyltransferases have been determined (Fig. 3) (75Long S.B. Casey P.J. Beese L.S. Reaction path of protein farnesyltransferase at atomic resolution.Nature. 2002; 419: 645-650Crossref PubMed Scopus (160) Google Scholar, 76Taylor J.S. Reid T.S. Terry K.L. Casey P.J. Beese L.S. Structure of mammalian protein geranylgeranyltransferase type-I.EMBO J. 2003; 22: 5963-5974Crossref PubMed Scopus (103) Google Scholar). Kinetic studies suggest an ordered binding mechanism in FTase, in which FPP binds to the apo enzyme first, followed by the CaaX substrate (77Pompliano D.L. Schaber M.D. Mosser S.D. Omer C.A. Shafer J.A. Gibbs J.B. Isoprenoid diphosphate utilization by recombinant human farnesyl:protein transferase: interactive binding between substrates and a preferred kinetic pathway.Biochemistry. 1993; 32: 8341-8347Crossref PubMed Google Scholar, 78Furfine E.S. Leban J.J. Landavazo A. Moomaw J.F. Casey P.J. Protein farnesyltransferase: kinetics of farnesyl pyrophosphate binding and product release.Biochemistry. 1995; 34: 6857-6862Crossref PubMed Google Scholar, 79Yokoyama K. Zimmerman K. Scholten J. Gelb M.H. Differential prenyl pyrophosphate binding to mammalian protein geranylgeranyltransferase-I and protein farnesyltransferase and its consequences on the specificity of protein prenylation.J. Biol. Chem. 1997; 272: 3944-3952Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 80Hightower K.E. Huang C-C. Casey P.J. Fierke C.A. H-ras peptide and protein substrates bind protein farnesyltransferase as an ionized thiolate.Biochemistry. 1998; 37: 15555-15562Crossref PubMed Scopus (95) Google Scholar). The release of farnesylated product is the rate-limiting step of the reaction and occurs only in the presence of excess of either substrate, particularly isoprenoid diphosphate (3Reiss Y. Goldstein J.L. Seabra M.C. Casey P.J. Brown M.S. Inhibition of purified p21ras farnesyl:protein transferase by Cys-AAX tetrapeptides.Cell. 1990; 62: 81-88Abstract Full Text PDF PubMed Scopus (687) Google Scholar, 8Pompliano D.L. Rands E. Schaber M.D. Mosser S.D. Anthony N.J. Gibbs J.B. Steady-state kinetic mechanism of ras farnesyl:protein transferase.Biochemistry. 1992; 31: 3800-3807Crossref PubMed Scopus (244) Google Scholar, 78Furfine E.S. Leban J.J. Landavazo A. Moomaw J.F. Casey P.J. Protein farnesyltransferase: kinetics of farnesyl pyrophosphate binding and product release.Biochemistry. 1995; 34: 6857-6862Crossref PubMed Google Scholar, 81Huang C-C. Casey P.J. Fierke C.A. Evidence for a catalytic role of zinc in protein farnesyltransferase: spectroscopy of Co2+-FTase indicates metal coordination of the substrate thiolate.J. Biol. Chem. 1997; 272: 20-23Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 82Tschantz W.R. Furfine E.S. Casey P.J. Substrate binding is required for release of product from mammalian protein farnesyltransferase.J. Biol. Chem. 1997; 272: 9989-9993Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar). This reaction cycle effectively maintains FTase in a substrate- or product-bound complex at all times. Although the GGTase-I reaction has not been studied in such detail, available evidence indicates that it proceeds through a similar pathway (83Yokoyama K. McGeady P. Gelb M.H. Mammalian protein geranylgeranyltransferase-I: substrate specificity, kinetic mechanism, metal requirements, and affinity labeling.Biochemistry. 1995; 34: 1344-1354Crossref PubMed Google Scholar, 84Stirtan W.G. Poulter C.D. Yeast protein geranylgeranyltransferase type-I: steady-state kinetics and substrate binding.Biochemistry. 1997; 36: 4552-4557Crossref PubMed Scopus (25) Google Scholar). FTase and GGTase-I exist as αβ heterodimers and share a common α subunit (48 kDa molecular mass) (16Seabra M.C. Reiss Y. Casey P.J. Brown M.S. Goldstein J.L. Protein farnesyltransferase and geranylgeranyltransferase share a common alpha subunit.Cell. 1991; 65: 429-434Abstract Full Text PDF PubMed Scopus (293) Google Scholar, 30Chen W-J. Andres D.A. Goldstein J.L. Brown M.S. Cloning and expression of a cDNA encoding the alpha subunit of rat p21ras protein farnesyltransferase.Proc. Natl. Acad. Sci. USA. 1991; 88: 11368-11372Crossref PubMed Google Scholar) and a homologous β subunit (46 kDa in FTase, 42 kDa in GGTase-I) (3Reiss Y. Goldstein J.L. Seabra M.C. Casey P.J. Brown M.S. Inhibition of purified p21ras farnesyl:protein transferase by Cys-AAX tetrapeptides.Cell. 1990; 62: 81-88Abstract Full Text PDF PubMed Scopus (687) Google Scholar, 19Moomaw J.F. Casey P.J. Mammalian protein geranylgeranyltransferase: subunit composition and metal requirements.J. Biol. Chem. 1992; 267: 17438-17443Abstract Full Text PDF PubMed Google Scholar, 21Yokoyama K. Gelb M.H. Purification of a mammalian protein geranylgeranyltransferase: formation and catalytic properties of an enzyme-geranylgeranyl dipho
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