- Protein family review
- Open Access
© BioMed Central Ltd 2003
- Published: 1 April 2003
Three different protein prenyltransferases (farnesyltransferase and geranylgeranyltransferases I and II) catalyze the attachment of prenyl lipid anchors 15 or 20 carbons long to the carboxyl termini of a variety of eukaryotic proteins. Farnesyltransferase and geranylgeranyltransferase I both recognize a 'Ca1a2X' motif on their protein substrates; geranylgeranyltransferase II recognizes a different, non-CaaX motif. Each enzyme has two subunits. The genes encoding CaaX protein prenyltransferases are considerably longer than those encoding non-CaaX subunits, as a result of longer introns. Alternative splice forms are predicted to occur, but the extent to which each splice form is translated and the functions of the different resulting isoforms remain to be established. Farnesyltransferase-inhibitor drugs have been developed as anti-cancer agents and may also be able to treat several other diseases. The effects of these inhibitors are complicated, however, by the overlapping substrate specificities of geranylgeranyltransferase I and farnesyltransferase.
- Carboxyl Terminus
Features of human protein prenyltransferases
Geranylgeranyltransferase I (GGT1)
Geranylgeranyltransferase II (GGT2 or RabGGT)
Gene name (α subunit)
Gene name (β subunit)
Carboxy-terminal -Ca1a2X box*
Carboxy-terminal -Ca1a2X box*
Carboxy-terminal motif such as -CC, -CXC, -CCX, -CCXX, -CCXXX, or -CXXX†
Automatic comparisons of data from expressed sequence tags (ESTs) with genes (for example using the program Acembly, for which the results are available from the NCBI AceView server ) shows that all the human protein prenyltransferase genes have multiple alternative splice variants. The extent of translation of the various predicted transcripts and the structures and functions of the resulting proteins remain to be established experimentally; some of the predicted transcripts may be derived from missplicing rather than being real splice variants.
Protein prenyltransferase genes in model organisms
Number of exons
The α subunits of protein prenyltransferases consist of tetratricopeptide repeats and are part of the tetratricopeptide repeat superfamily , which also includes functionally diverse proteins involved in transcription, co-chaperoning, protein transport, cell-cycle control and phosphorylation. Although evolution of repeat proteins is difficult to analyze and interpret, Zhang and Grishin  have deduced convincingly that the FNTA and RABGGTA genes originated from a common ancestor that already contained multiple tetratricopeptide repeats rather than having independently amplified the number of motifs as the families diverged over time.
It is difficult to estimate the effect of alternative splicing on the structure of protein prenyltransferases. We would expect that the integrity of the structure of the β subunits would be more sensitive to non-terminal truncations than are the α subunits, because the modular structure of the tetratricopeptide repeat motifs in the α subunits would allow truncations and additions without severe consequences for the hydrophobic packing of the structure.
CaaX prenyltransferases recognize the carboxy-terminal Ca1a2X motif (see Table 1) [23, 24] of substrate proteins, usually after binding farnesyl-pyrophosphate  or geranylgeranylpyrophosphate . The lipid anchors are then transferred by a catalytic mechanism that depends on formation of a complex between a Zn2+ cation and the cysteine of the Ca1a2X motif . High concentrations of Mg2+ are required for optimal enzymatic activity of FT , though this is apparently not the case for GGT1 . The Zn2+ is suggested to be required for the proper conformation of the substrate peptide . The major conformational change in the transfer step seems to be a rotation of the prenylpyrophosphate in the binding pocket and not of parts of the enzyme itself. A detailed picture of the reaction pathway that involves electrophilic and nucleophilic mechanisms is given by a series of structures representing the different states  as well as by kinetic measurements .
In contrast to FT and GGT1, GGT2 does not require a very specific carboxy-terminal motif  apart from the availability of several cysteines close to the carboxyl terminus that are often arranged -CC, -CXC, -CCX, -CCXX, -CCXXX or, in a few cases, with only a single cysteine as in -CXXX. If the motif consists of two cysteines in close proximity, two geranylgeranyl moieties are usually added.
GGT2 recognizes the structural features of a complex of the substrate with an escort protein (Rab escort protein (REP), previously known as component A) and then scans the carboxyl terminus for prenylatable cysteines . The catalytic mechanism of lipid transfer from geranylgeranylpyrophosphate to the protein substrate also requires Zn2+, and the following model has been presented for how the double geranylgeranylation could take place on the basis of insights from the reaction pathway of FT . After attachment of the first prenyl group, the lipid chain is translocated over the enzyme surface into another hydrophobic groove upon binding of the second geranylgeranylpyrophosphate. Finally, binding of a third geranylgeranylpyrophosphate releases the whole complex of the now doubly geranylgeranylated substrate with its escort protein; the escort protein is also involved in the transport of the substrate to the target membrane [31, 32].
Localization and function
The results of systematic oligonucleotide microarray experiments catalogued in the human gene-expression index database [33, 34] show that protein prenyltransferases are expressed in a variety of tissues. Both CaaX prenyltransferases seem to be active (that is, their α and β subunits are coexpressed) in a range of tissues, and the non-CaaX prenyltransferase subunits are also expressed in several more tissues. It should be noted, however, that many of the expression levels listed [33, 34] are close to the detection threshold and could therefore result from cross-hybridization between close homologs rather than true expression. Interestingly, the α subunits also appear to be expressed in tissues that lack expression of the corresponding β subunits; this suggests that single subunits, or isoforms of them, might have additional, prenylation-independent functions in the cell.
As the α subunit of CaaX prenyltransferases is shared between FT and GGT1, its expression must be higher than that of each β subunit if it is to form 1:1 complexes with the β subunits of both enzymes. These higher expression levels seem to be transcriptionally regulated by different promoters; in order to produce recombinant CaaX prenyltransferases in the laboratory, it is thus necessary to downregulate expression of the α subunits when coexpressing with β subunits .
Lipid anchors are common posttranslational modifications that can direct the subcellular localization of proteins. Other lipid modifications, such as myristoylation [36–38], palmitoylation [39, 40] and glycosylphosphatidylinositol (GPI) anchors [41, 42], are mainly important for attachment of the protein to membranes, but lipid modification by protein prenyltransferases seems to have a more complex role: the farnesyl and geranylgeranyl moieties attached to the substrates are directly involved in protein-protein interactions as well as in protein-membrane interactions . The importance of protein prenyltransferases is illustrated by the involvement of their substrates in critical cellular pathways and diseases .
Substrates and functions of CaaX prenyltransferases
Typical substrates that are farnesylated by FT include many members of the Ras superfamily of small GTPases (H-Ras, K-Ras, N-Ras, Ras2, Rap2, RhoB (which is also geranylgeranylated), RhoE, Rheb, TC10, and TC21), as well as the nuclear lamina proteins lamin A and B, the kinetochore proteins CENP-E and CENP-F, fungal mating factors, cGMP phosphodiesterase α, γ subunit variants of G proteins, DnaJ heat-shock protein homologs, rhodopsin kinase, the peroxisomal membrane proteins Pex19 and PxF and paralemmin (a neural protein suggested to be involved in membrane dynamics). GGT1 preferentially geranylgeranylates some of the other small GTPases (such as Rac1, Rac2, RalA, Rap1A, Rap1B, RhoA, and RhoB (which is also farnesylated, as noted above), RhoC, Cdc42, Rab8 (which is also geranylgeranylated by GGT2), Rab11, and Rab13, as well as some γ-subunit variants of G proteins, cGMP phosphodiesterase β and the plant calmodulin CaM53. Typically, prenylation by CaaX protein prenyltransferases is accompanied by further posttranslational processing, most often involving cleavage of the carboxy-terminal tripeptide (-a1a2X) followed by carboxymethylation of the carboxyl terminus [45–47]. Palmitoylation is another modification that sometimes takes place after prenylation .
Because several prenylated substrates are involved in diseases, inhibition of protein prenyltransferases has great potential for medical applications. A boom in the field was triggered by the finding that inhibition of FT in mice that have tumors derived from H-Ras-transformed cells leads to tumor regression, while the inhibitor has no adverse effect on the organism . This led to successful completion of clinical phase I trials of farnesyl transferase inhibitors (FTIs), but in phase II trials the efficacy of the inhibitors towards a broad spectrum of different cancer cells (such as K-Ras-transformed cells) was far below the high expectations that arose from the phase I trials. Surprisingly, however, beneficial effects were found for other, non-neoplastic diseases; for example, diabetic retinopathy and macular degeneration . The unexpected physiological effects of FT inhibition are partly due to a striking cross-specificity between the two CaaX prenyltransferases: both FT and GGT1 can use either farnesyl-pyrophosphate or GGPP to a certain extent to transfer lipids to several of each others' substrates as well as their own [51, 52], and several substrates can be either farnesylated or geranylgeranylated. The substrates probably compete in vivo for the enzymes loaded with the preferred polyprenylpyrophosphate, and the type of modification that is added depends on the relative affinity of the substrates for the enzymes.
Substrates and functions of non-CaaX prenyltransferases
The main substrates for prenylation by GGT2 are the Rab family of proteins, the largest group of small GTPases in the Ras superfamily. There are at least 60 different Rabs in humans . They interact with the Rab escort protein REP, which is required for the prenylation of Rabs by GGT2 , and are involved in the docking of transport vesicles to their specific target membranes .
As with CaaX protein prenyltransferases, deficiencies in prenylation by non-CaaX protein prenyltransferases are relevant to diseases [59, 60]. A mutation inactivating a start codon of the major transcript of the α subunit of GGT2 is one of the many mutations involved in the recessively inherited Hermansky-Pudlak syndrome and related disorders [61, 62], in which platelet synthesis, platelet organelle function and pigmentation are affected. X-linked choroideremia (CHM) results in retinal degeneration, with symptoms starting from night blindness in young people and progressing over decades until vision is completely lost . It is caused by loss-of-function mutations in the CHM gene, which encodes Rab escort protein 1 (REP1) . Loss-of function mutations in the Rab27a gene cause Griscelli syndrome, whose symptoms are similar to Hermansky-Pudlak syndrome and other diseases associated with insufficient Rab prenylation .
There are several issues that merit further study in the regulation of protein prenyltransferases. Firstly, it is not clear how the concomitant transcription of the two subunits from two different chromosomes is regulated or where and how the subunits meet to build up functional prenyltransferases. Secondly, given that there are multiple splice variants, it is likely that additional variants of subunits will be found to have distinct functions or regulatory roles; an example is a variant of the FT/GGT1 α subunit that has been reported to be directly involved in signaling by transforming growth factor β and activin . Interpretation of results in areas ranging from molecular biology to clinical trials must take into account possible isoforms with varying functions or altered interactions to avoid erroneous conclusions.
A third issue is the striking differences in gene size and intron length between the two types of protein prenyltransferases. One of several possible factors that could have caused this is a difference in evolutionary selection pressures. Whereas FT and GGT1 partly compensate each other functionally, there is no counterpart for GGT2. Furthermore, formation of a complex between the substrate and an escort protein is necessary for recognition by GGT2 and the conservation of additional binding sites at the surface is therefore required. Also, the severity of the effect when the prenylation of different substrates is abolished may vary. Finally, the size of the genomic region containing the gene might alter its accessibility to the transcription machinery and the time needed to complete transcription, so gene size may affect or be affected by expression levels. The implications of these factors for the exact evolutionary history of the protein prenyltransferase genes (such as the relative ages of the subunits and the order of duplication events) remain to be established.
Finally, more research is also needed on the effects of FTIs. After the rush to develop inhibitors, basic research is now needed as well as clinical trials in order to improve the understanding of the basic processes involved . For example, it cannot be ruled out that some effects of FTIs are not a direct consequence of inhibiting prenylation but are instead due to cross-reactivity with proteins from completely different pathways. It is tempting to speculate that one of the proteins that are evolutionarily related to the protein prenyltransferases (such as other prenyltransferases) could be affected by FTIs; the selectivity of existing FTIs, which do not inhibit even the much more closely related GGTs, makes this scenario most unlikely, however. The next task is to identify clearly the proteins whose altered prenylation causes the observed effects of FT inhibition. Given the multiplicity and heterogeneity of these effects, it is clear that they cannot be attributed to one single farnesylated protein that lacks a lipid modification because of FT inhibition; rather, alterations in the function of several proteins probably cause the observed effects, with variations depending on the cell type, disease and organism. Further research may eventually lead to FTIs being used successfully to treat cancers and other diseases.
The authors are grateful for useful comments from Maria Novatchkova and Alexander Schleiffer as well as for continuous support from Boehringer Ingelheim. This project has been partly funded by the Fonds zur Förderung der wissenschaftlichen Forschung Österreichs (FWF grant P15037) and by the Austrian National Bank (OeNB).
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