Prenylation (also known asisoprenylation orlipidation) is the addition ofhydrophobic molecules to aprotein or abiomolecule. It is usually assumed thatprenyl groups (3-methylbut-2-en-1-yl) facilitate attachment tocell membranes, similar tolipid anchors like theGPI anchor, though direct evidence of this has not been observed. Prenyl groups (also called isoprenyl groups, having one hydrogen atom more thanisoprene) have been shown to be important for protein–protein binding through specialized prenyl-binding domains.
Protein prenylation involves the transfer of either afarnesyl or ageranylgeranyl moiety to C-terminalcysteine(s) of the target protein. There are three enzymes that carry out prenylation in the cell, farnesyl transferase, Caax protease and geranylgeranyl transferase I.[1]
Farnesylation is a type of prenylation, a post-translational modification of proteins by which an isoprenyl group is added to a cysteine residue.[2] It is an important process to mediate protein–protein interactions and protein–membrane interactions.[3]
There are at least 3 types of sites that are recognized by prenylation enzymes. TheCaaX motif is found at the COOH-terminus of proteins, such aslamins or Ras. The motif consists of acysteine (C), two aliphatic amino acids ("aa") and some other terminal amino acid ("X"). If the X position isserine,alanine, ormethionine, the protein is farnesylated. For instance, inrhodopsin kinase the sequence is CVLS. If X isleucine, the protein is geranylgeranylated.[4] The second motif for prenylation isCXC, which, in the Ras-related protein Rab3A, leads to geranylgeranylation on both cysteine residues and methyl esterification.[4] The third motif,CC, is also found in Rab proteins, where it appears to direct only geranylgeranylation but not carboxyl methylation.[4] Carboxyl methylation only occurs on prenylated proteins.[4]
Farnesyltransferase andgeranylgeranyltransferase I are very similar proteins. They consist of two subunits, the α-subunit, which is common to both enzymes, and the β-subunit, whose sequence identity is just 25%. These enzymes recognise theCaaX box at the C-terminus of the target protein.C is the cysteine that is prenylated,a is any aliphatic amino acid, and the identity ofX determines which enzyme acts on the protein. Farnesyltransferase recognizesCaaX boxes where X = M, S, Q, A, or C, whereas geranylgeranyltransferase I recognizes CaaX boxes with X = L or E.
Rab geranylgeranyltransferase, or geranylgeranyltransferase II, transfers (usually) two geranylgeranyl groups to the cysteine(s) at the C-terminus ofRab proteins. The C-terminus of Rab proteins varies in length and sequence and is referred to as hypervariable. Thus Rab proteins do not have a consensus sequence, such as the CAAX box, which the Rab geranylgeranyl transferase can recognize. The Rab proteins usually terminate in a CC or CXC motif. Instead, Rab proteins are bound by theRab escort protein (REP) over a more conserved region of the Rab protein and then presented to the Rab geranylgeranyltransferase. Once Rab proteins are prenylated, the lipid anchor(s) ensure that Rabs are no longer soluble. REP, therefore, plays an important role in binding and solubilising the geranylgeranyl groups and delivers the Rab protein to the relevant cell membrane.
Both isoprenoid chains,geranylgeranyl pyrophosphate (GGpp) andfarnesyl pyrophosphate are products of theHMG-CoA reductase pathway. The product of HMG CoA reductase is mevalonate. By combining precursors with 5 carbons, the pathway subsequently produces geranyl pyrophosphate (10 carbons), farnesyl pyrophosphate (15 carbons) and geranylgeranyl pyrophosphate (20 carbons). Two farnesyl pyrophosphate groups can also be combined to form squalene, the precursor forcholesterol. This means thatstatins, which inhibit HMG CoA reductase, inhibit the production of both cholesterol and isoprenoids.
Note that, in the HMG-CoA reductase/mevalonate pathway, the precursors already contain a pyrophosphate group, and isoprenoids are produced with a pyrophosphate group. There is no known enzyme activity that can carry out the prenylation reaction with the isoprenoid alcohol. However, enzymatic activity for isoprenoid kinases capable converting isoprenoid alcohols to isoprenoid pyrophosphates have been shown.[5] In accordance with this,farnesol andgeranylgeraniol have been shown to be able to rescue effects caused by statins or nitrogenousbisphosphonates, further supporting that alcoholscan be involved in prenylation, likely via phosphorylation to the corresponding isoprenoid pyrophosphate.
Proteins that undergo prenylation includeRas, which plays a central role in the development of cancer. This suggests that inhibitors of prenylation enzymes (e.g.,farnesyltransferase) may influence tumor growth. In the case of the K- and N-Ras forms of Ras, when cells are treated withFTIs, these forms of Ras can undergo alternate prenylation in the form of geranylgeranylation.[6] Recent work has shown thatfarnesyltransferase inhibitors (FTIs) also inhibit Rab geranylgeranyltransferase and that the success of such inhibitors in clinical trials may be as much due to effects onRab prenylation as on Ras prenylation. Inhibitors of prenyltransferase enzymes display different specificity for the prenyltransferases, dependent upon the specific compound being utilized.
In addition to GTPases, the protein kinaseGRK1 also known asrhodopsin kinase (RK) has been shown to undergo farnesylation and carboxyl methylation directed by the carboxyl terminal CVLS CaaX box sequence of the protein.[7] The functional consequence of these post-translational modifications have been shown to play a role in regulating the light-dependent phosphorylation ofrhodopsin, a mechanism involved in light adaptation.[8]
FTIs can also be used to inhibit farnesylation inparasites such asTrypanosoma brucei andmalaria. Parasites seem to be more vulnerable to inhibition of farnesyltransferase than humans are. In some cases, this may be because they lack geranylgeranyltransferase I. Thus, it may be possible for the development of antiparasitic drugs to 'piggyback' on the development of FTIs for cancer research.
In addition, FTIs have shown some promise in treating a mouse model ofprogeria, and in May 2007 a phase II clinical trial using the FTIlonafarnib was started for children with progeria.[9]
In signal transduction via G protein,palmitoylation of the α subunit, prenylation of the γ subunit, andmyristoylation is involved in tethering the G protein to the inner surface of the plasma membrane so that the G protein can interact with its receptor.[10]
Small molecules can also undergo prenylation, such as in the case ofprenylflavonoids and othermeroterpenoids. Prenylation of a vitamin B2 derivative (flavin mononucleotide) was recently described.[11]
A 2012 study found that statin treatment increases lifespan and improves cardiac health inDrosophila by decreasing specific protein prenylation. The study concluded, "These data are the most direct evidence to date that decreased protein prenylation can increase cardiac health and lifespan in any metazoan species, and may explain the pleiotropic (non-cholesterol related) health effects of statins."[12]
A 2012 clinical trial explored the approach of inhibiting protein prenylation with some degree of success in the treatment ofHutchinson–Gilford progeria syndrome, a multisystem disorder which causes failure to thrive and accelerated atherosclerosis leading to early death.[13][14]
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