Prenylation
Protein prenylation
Protein prenylation involves the transfer of either a
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]
Prenylation sites
There are at least 3 types of sites that are recognized by prenylation enzymes. The CaaX motif is found at the COOH-terminus of proteins, such as lamins or Ras. The motif consists of a cysteine (C), two aliphatic amino acids ("aa") and some other terminal amino acid ("X"). If the X position is serine, alanine, or methionine, the protein is farnesylated. For instance, in rhodopsin kinase the sequence is CVLS. If X is leucine, the protein is geranylgeranylated.[4] The second motif for prenylation is CXC, 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 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. Farnesyltransferase recognizes CaaX boxes where X = M, S, Q, A, or C, whereas geranylgeranyltransferase I recognizes CaaX boxes with X = L or E.
Rab geranylgeranyl transferase
Rab geranylgeranyltransferase, or geranylgeranyltransferase II, transfers (usually) two geranylgeranyl groups to the cysteine(s) at the C-terminus of
Substrates
Both isoprenoid chains,
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.
Proteins that undergo prenylation include
In addition to GTPases, the protein kinase
Inhibitors
FTIs can also be used to inhibit farnesylation in parasites such as Trypanosoma brucei and malaria. 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 of progeria, and in May 2007 a phase II clinical trial using the FTI lonafarnib was started for children with progeria.[9]
In signal transduction via G protein, palmitoylation of the α subunit, prenylation of the γ subunit, and myristoylation 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]
Prenylation of small molecules
Longevity and cardiac effects
A 2012 study found that statin treatment increases lifespan and improves cardiac health in Drosophila 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 of
See also
- Myristoylation
- Palmitoylation
- Choroideremia, a genetic disease caused by the loss of REP1, REP2 almost compensates, but cannot rescue the slow onset of blindness
References
- PMID 8621375.
- S2CID 17511637.
- S2CID 11555502.
- ^ PMID 8456312.
- PMID 9606952.
- PMID 9162087.
- PMID 1730692.
- S2CID 4314755.
- ^ Kleinman, Monica E. (11 June 2019). "Phase II trial of Lonafarnib (a farnesyltransferase inhibitor) for progeria".
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(help) - PMID 8521505.
- PMID 26083748.
- PMID 22737247.
- PMID 23012407.
- PMID 23390246.
Further reading
- Maurer-Stroh, Sebastian; Eisenhaber, Frank (2005). "Refinement and prediction of protein prenylation motifs". PMID 15960807.
- Magee A, Seabra M (2003). "Are prenyl groups on proteins sticky fingers or greasy handles?". Biochem J. 376 (Pt 2): e3–4. PMID 14627432.
- Taylor J, Reid T, Terry K, Casey P, Beese L (2003). "Structure of mammalian protein geranylgeranyltransferase type-I". EMBO J. 22 (22): 5963–74. PMID 14609943.
External links
- Prenylation at the U.S. National Library of Medicine Medical Subject Headings (MeSH)