Alternative titles; symbols
HGNC Approved Gene Symbol: FNTA
Cytogenetic location: 8p11.21 Genomic coordinates (GRCh38): 8:43,056,323-43,085,785 (from NCBI)
The FNTA gene encodes the alpha subunit for the heterodimeric enzymes CAAX farnesyltransferase and CAAX geranylgeranyltransferase (Zhang et al., 1994). The beta subunits are encoded by the FNTB (134636) and PGGT1B (602031) genes, respectively.
Eukaryotic cells contain 3 distinct prenyltransferases that attach either a farnesyl group (15 carbons) or a geranylgeranyl group (20 carbons) in thioether linkage to C-terminal cysteine residues in a variety of cellular proteins (Schafer and Rine, 1992). These posttranslational modifications provide a mechanism for membrane localization of proteins that lack a transmembrane domain. Prenylation is a frequent covalent modification of proteins; Epstein et al. (1991) estimated that approximately 0.5% of all proteins in mammalian tissues are prenylated. The best characterized of the prenyltransferases, CAAX farnesyltransferase (FTase), attaches a farnesyl group from farnesyl pyrophosphate to cysteine residues at the fourth position from the C terminus of proteins that end in the so-called CAAX box, where C is cysteine, A is usually but not always an aliphatic amino acid, and X is typically methionine or serine. This enzyme has the remarkable property of farnesylating peptides as short as 4 residues in length that conform to the CAAX consensus sequence (summary by Andres et al., 1993).
Epstein et al. (1991) noted that full-length cDNAs for the alpha and beta subunits of the rat farnesyltransferase were cloned, and both were shown to be essential for catalytic activity. Andres et al. (1993) used the rat cDNAs to clone cDNAs for the human alpha and beta (134636) subunits. The human and rat amino acid sequences show 93% identity for the alpha subunit and 96% identity for the beta subunit.
CAAX farnesyltransferase is an alpha-beta heterodimeric enzyme with a molecular mass of approximately 100 kD. Geranylgeranyltransferase type I (GGTase-I) is also a heterodimeric enzyme. Zhang et al. (1994) analyzed tryptic digests of the bovine GGTase-I alpha subunit and showed that it is identical to that of bovine FTase; GGTase-I uses a different beta chain (PGGT1B; 602031). Coexpression of human PGGT1B and FNTA cDNAs in E. coli produced recombinant GGTase-I with electrophoretic and enzymatic properties indistinguishable from those of native GGTase-I. The beta chains of both FTase (FNTB; 134636) and GGTase are catalytic for specific substrates (e.g., p21ras; see 190020).
A role for the alpha subunit had been uncertain until Wang et al. (1996) showed, using the 2-hybrid yeast assay, that FNTA is a specific cytoplasmic interactor of the transforming growth factor-beta (190180) and activin type I (102576) receptors. Wang et al. (1996) stated that because of these interactions FNTA is likely to be a key component of the signaling pathway which involves p21ras, an important substrate for farnesyltransferase. Membrane localization and activity of RAS is dependent on farnesylation; Wang et al. (1996) proposed that the actions of TGF-beta and activin on cell growth may be mediated through their ability to affect ras farnesylation via FNTA.
Long et al. (2002) presented a complete series of structures representing the major steps along the reaction coordinate of the enzyme protein farnesyltransferase. From these observations, Long et al. (2002) deduced the determinants of substrate specificity and an unusual mechanism in which product release requires binding of substrate, analogous to classically processive enzymes. A structural model for the transition state consistent with previous mechanistic studies was also constructed.
By Southern blot hybridization and PCR analyses of panels of human/Chinese hamster somatic cell hybrid lines and by fluorescence chromosomal in situ hybridization, Andres et al. (1993) mapped the FNTA gene to 8p22-q11. Two genes related to FNTA were also identified: FNTAL1 (FNTAP1) was assigned to 11q13.4-q14.1 and FNTAL2 (FNTAP2) to chromosome 13.
Using interspecific backcross analysis, Porter and Messer (1996) mapped the Fnta gene to mouse chromosome 8.
Andres, D. A., Milatovich, A., Ozcelik, T., Wenzlau, J. M., Brown, M. S., Goldstein, J. L., Francke, U. cDNA cloning of the two subunits of human CAAX farnesyltransferase and chromosomal mapping of FNTA and FNTB loci and related sequences. Genomics 18: 105-112, 1993. [PubMed: 8276393] [Full Text: https://doi.org/10.1006/geno.1993.1432]
Epstein, W. W., Lever, D., Leining, L. M., Bruenger, E., Rilling, H. C. Quantitation of prenylcysteines by a selective cleavage reaction. Proc. Nat. Acad. Sci. 88: 9668-9670, 1991. [PubMed: 1946384] [Full Text: https://doi.org/10.1073/pnas.88.21.9668]
Long, S. B., Casey, P. J., Beese, L. S. Reaction path of protein farnesyltransferase at atomic resolution. Nature 419: 645-650, 2002. [PubMed: 12374986] [Full Text: https://doi.org/10.1038/nature00986]
Porter, J. C., Messer, A. Genetic mapping of farnesyltransferase alpha(Fnta) to mouse chromosome 8. Mammalian Genome 7: 622-623, 1996. [PubMed: 8678990] [Full Text: https://doi.org/10.1007/s003359900186]
Schafer, W. R., Rine, J. Protein prenylation: genes, enzymes, targets, and functions. Annu. Rev. Genet. 26: 209-237, 1992. [PubMed: 1482112] [Full Text: https://doi.org/10.1146/annurev.ge.26.120192.001233]
Wang, T., Danielson, P. D., Li, B., Shah, P. C., Kim, S. D., Donahoe, P. K. The p21ras farnesyltransferase alpha subunit in TGF-beta and activin signaling. Science 271: 1120-1122, 1996. [PubMed: 8599089] [Full Text: https://doi.org/10.1126/science.271.5252.1120]
Zhang, 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. 269: 3175-3180, 1994. [PubMed: 8106351]