Protein family review

This in an extract of a protein family review which first appeared in GenomeBiology, and is reproduced by permission of the publisher, BioMedCentral Ltd.

Authors:

Sebastian Maurer-Stroh, Stefan Washietl and Frank Eisenhaber

Research Institute of Molecular Pathology, Dr Bohr-Gasse 7, A-1030 Vienna, Austria

Correspondence:

Sebastian Maurer-Stroh.

Email:

stroh@imp.univie.ac.at

Read the full article

Subscribers to GenomeBiology may view the full version of this review article online at http://genomebiology.com/2003/4/4/212

Published:

1 April 2003

Protein prenyltransferases

Summary

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.

Frontiers

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 [65]. 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 [66]. 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 structural relationship between protein prenyltransferase β subunits and squalene-hopene cyclases

The complete structure of rat FT (PDB identifier 1D8D