"Prenyl-" the functional group
Prenylation, or isoprenylation, or lipidation is the addition of hydrophobic molecules to a protein. It is usually assumed that prenyl groups (3-methyl-but-2-en-1-yl) facilitate attachment to cell membranes, similar to lipid anchor like the GPI anchor, though direct evidence is missing. Prenyl groups have been shown to be important for protein-protein binding through specialized prenyl-binding domains.
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Contents
- 1 Protein prenylation
- 1.1 Farnesyltransferase and geranylgeranyltransferase I
- 1.2 Rab geranylgeranyl transferase
- 2 See also
- 3 References
- 4 External links
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Protein prenylation
Protein prenylation involves the transfer of either a farnesyl or a geranyl-geranyl moiety to C-terminal cysteine(s) of the target protein. There are three enzymes that carry out prenylation in the cell, farnesyl transferase, Caax protease and methyl transferase.
Farnesylation is a type of prenylation, a posttraductional modification of proteins by which a isoprenil group is added to a cysteine residue.[1] It is an important process to mediate protein-protein interactions and protein-membrane interactions.[2]
Farnesyltransferase and geranylgeranyltransferase I
Farnesyltransferase and Geranylgeranyltransferase 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 the CaaX 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 of X determines which enzyme acts on the protein. Work reported in the journal Genome Biology in 2005 reports refinement of computational detection methods for identification of protein prenylation motifs and establishment of an on-line analysis facility entitled "PrePS".[1]
Rab geranylgeranyl transferase
Rab geranylgeranyltransferase, or Geranylgeranyl transferase II, transfers (usually) two geranylgeranyl groups to the cystein(s) at the C-terminus of Rab 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. Instead, Rab proteins are bound by the Rab 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) and farnesyl pyrophosphate are products of the HMG-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 for cholesterol. This means that statins, 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 diphosphates have been shown .[3] In accordance with this, farnesol and geranylgeraniol have been shown to be able to rescue effects caused by statins or nitrogenous bisphosphonates, further supporting that alcohols can be involved in prenylation, likely via phosphorylation to the corresponding isoprenoid diphosphate.
Proteins that undergo prenylation include Ras, 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 with FTIs, these forms of Ras can undergo alternate prenylation in the form of geranylgeranylation.[4] Recent work has shown that farnesyltransferase inhibitors (FTIs) also inhibit Rab geranylgeranyltransferase and that the success of such inhibitors in clinical trials may be as much due to effects on Rab prenylation as on Ras prenylation. It should be noted that inhibitors of prenyltransferase enzymes display different specificity for the prenyltransferases, dependent upon the specific compound being utilized.
FTIs can also be used to inhibit farnesylation in parasites such as trypansoma brucii and malaria. Parasites seem to be more vulnerable to inhibition of Farnesyl transferase than humans are. In some cases, this may be because they lack Geranylgeranyltransferase I. Thus, it may be possible for the development of antiparastic drugs to 'piggyback' on the development of FTIs for cancer research.
In addition, FTIs have shown some promise in treating a mouse model of progeria, and in May 2007 a phase II clinical trial using the FTI Lonafarnib was started for children with progeria.[5]
See also
- Myristoylation
- Palmitoylation
- Choroideremia, a genetic disease caused by the loss of REP1, REP2 almost conmpensates, but cannot rescue the slow onset of blindness
References
- ^ 1. Maltese WA. Posttranslational modification of proteins by isoprenoids in mammalian cells. FASEB J. 1990 Dec;4(15):3319-28.
- ^ Novelli G, D'Apice MR. Protein farnesylation and disease. J Inherit Metab Dis. 2012 Feb 4.
- ^ Bentinger, M.; Grünler, J.; Peterson, E.; Swiezewska, E.; Dallner, G. (1998). "Phosphorylation of farnesol in rat liver microsomes: properties of farnesol kinase and farnesyl phosphate kinase.". Archives of biochemistry and biophysics 353 (2): 191–198. DOI:10.1006/abbi.1998.0611. PMID 9606952. edit
- ^ Whyte, D.; Kirschmeier, P.; Hockenberry, T.; Nunez-Oliva, I.; James, L.; Catino, J.; Bishop, W.; Pai, J. (1997). "K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors". The Journal of Biological Chemistry 272 (22): 14459–14464. PMID 9162087. edit
- ^ Makar, AB; McMartin, KE; Palese, M; Tephly, TR (1975). "Phase II trial of Lonafarnib (a farnesyltransferase inhibitor) for progeria". Biochemical medicine 13 (2): 117–26. PMID ls1. http://clinicaltrials.gov/ct2/show/NCT00425607?term=progeria&rank=2.
- ^ Sebastian Maurer-Stroh and Frank Eisenhaber (2005). "Refinement and prediction of protein prenylation motifs". Genome Biology. 6:R55.
- Magee A, Seabra M (2003). "Are prenyl groups on proteins sticky fingers or greasy handles?". Biochem J 376 (Pt 2): e3–4. DOI:10.1042/BJ20031531. PMC 1223795. PMID 14627432. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1223795.
- Taylor J, Reid T, Terry K, Casey P, Beese L (2003). "Structure of mammalian protein geranylgeranyltransferase type-I". EMBO J 22 (22): 5963–74. DOI:10.1093/emboj/cdg571. PMC 275430. PMID 14609943. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=275430.
External links
- Prenylation at the US National Library of Medicine Medical Subject Headings (MeSH)
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Protein primary structure and posttranslational modifications
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| General |
Peptide bond · Protein biosynthesis · Proteolysis · Racemization · N-O acyl shift
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| N terminus |
Acetylation · Carbamylation · Formylation · Glycation · Methylation · Myristoylation (Gly)
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| C terminus |
Amidation · Glycosyl phosphatidylinositol (GPI) · O-methylation
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| Single specific AAs |
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Serine/Threonine
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Phosphorylation · Glycosylation · Methylidene-imidazolone (MIO) formation
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Tyrosine
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Phosphorylation · Sulfation · Porphyrin ring linkage · Adenylylation · Flavin linkage · Topaquinone (TPQ) formation
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Cysteine
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Palmitoylation · Prenylation
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Aspartate
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Succinimide formation
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Glutamate
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Carboxylation · Methylation · Polyglutamylation · Polyglycylation
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Asparagine
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Deamidation · Glycosylation
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Glutamine
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Transglutamination
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Lysine
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Methylation · Acetylation · Acylation · Adenylylation · Hydroxylation · Ubiquitination · Sumoylation · ADP-ribosylation · Deamination · Oxidative deamination to aldehyde · O-glycosylation · Imine formation · Glycation · Carbamylation
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Arginine
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Citrullination · Methylation · ADP-ribosylation
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Proline
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Hydroxylation
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Histidine
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Diphthamide formation · Adenylylation
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Tryptophan
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C-mannosylation
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| Crosslinks between two AAs |
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Cysteine-Cysteine
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Disulfide bond
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Methionine-Hydroxylysine
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Sulfilimine bond
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Lysine-Tyrosylquinone
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Lysine tyrosylquinone (LTQ) formation
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Tryptophan-Tryptophylquinone
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Tryptophan tryptophylquinone (TTQ) formation
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Three consecutive AAs
(Chromophore formation) |
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Serine–Tyrosine–Glycine
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p-Hydroxybenzylidene-imidazolinone formation
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Histidine–Tyrosine–Glycine
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4-(p-hydroxybenzylidene)-5-imidazolinone formation
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| Crosslinks between four AAs |
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Allysine-Allysine-Allysine-Lysine
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Desmosine
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←Amino acids
Secondary structure→
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