Misplaced Pages

#303696

21-502: As shown by Liu et al., lack of Zmpste24 prevents lamin A formation from its precursor farnesyl-prelamin A. Lack of ZMPSTE24 causes progeroid phenotypes in mice and humans. This lack increases DNA damage and chromosome aberrations and sensitivity to DNA-damaging agents that cause double-strand breaks. Also, lack of ZMPSTE24 allows an increase in non-homologous end joining , but a deficiency in steps leading to homologous recombinational DNA repair. This biochemistry article

42-502: 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

63-761: 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. The second motif for prenylation is CXC , which, in the Ras-related protein Rab3A, leads to geranylgeranylation on both cysteine residues and methyl esterification. The third motif, CC , is also found in Rab proteins, where it appears to direct only geranylgeranylation but not carboxyl methylation. Carboxyl methylation only occurs on prenylated proteins. Farnesyltransferase and geranylgeranyltransferase I are very similar proteins. They consist of two subunits,

84-555: Is a protein that in humans is encoded by the LMNA gene . Lamin A/C belongs to the lamin family of proteins. In the setting of ZMPSTE24 deficiency, the final step of lamin processing does not occur, resulting in an accumulation of farnesyl-prelamin A. In Hutchinson–Gilford progeria syndrome , a 50-amino acid deletion in prelamin A (amino acids 607–656) removes the site for the second endoproteolytic cleavage. Consequently, no mature lamin A

105-423: Is a stub . You can help Misplaced Pages by expanding it . LMNA 1IFR , 1IVT , 1X8Y , 2XV5 , 2YPT , 3GEF , 3V4Q , 3V4W , 3V5B 4000 16905 ENSG00000160789 ENSMUSG00000028063 P02545 P48678 NM_170707 NM_170708 NM_001002011 NM_001111102 NM_019390 NP_733821 NP_733822 NP_001002011 NP_001104572 NP_062263 Prelamin-A/C , or lamin A/C

126-455: Is an important process to mediate protein–protein interactions and protein–membrane interactions. 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

147-859: Is formed, and a farnesylated mutant prelamin A (progerin) accumulates in cells. The nuclear lamina consist of a two-dimensional matrix of proteins located next to the inner nuclear membrane . The lamin family of proteins make up the matrix and are highly conserved in evolution. During mitosis , the lamina matrix is reversibly disassembled as the lamin proteins are phosphorylated . Lamin proteins are thought to be involved in nuclear stability, chromatin structure and gene expression. Vertebrate lamins consist of two types, A and B. Through alternate splicing , this gene encodes three type A lamin isoforms. Early in mitosis, maturation promoting factor (abbreviated MPF, also called mitosis-promoting factor or M-phase-promoting factor) phosphorylates specific serine residues in all three nuclear lamins, causing depolymerization of

168-589: 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. Small molecules can also undergo prenylation, such as in the case of prenylflavonoids and other meroterpenoids . Prenylation of a vitamin B 2 derivative (flavin mononucleotide) was recently described. 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

189-563: Is the addition of hydrophobic molecules to a protein or a biomolecule . It is usually assumed that prenyl groups (3-methylbut-2-en-1-yl) facilitate attachment to cell membranes , similar to lipid anchors like the GPI anchor , though direct evidence of this has not been observed. Prenyl groups (also called isoprenyl groups, having one hydrogen atom more than isoprene ) have been shown to be important for protein–protein binding through specialized prenyl-binding domains. Protein prenylation involves

210-496: 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

231-444: The corresponding isoprenoid pyrophosphate. 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

SECTION 10

#1732883915304

252-553: The cysteine(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. The Rab proteins usually terminate in a CC or CXC motif. Instead, Rab proteins are bound by the Rab escort protein (REP) over

273-513: 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. In signal transduction via G protein, palmitoylation of the α subunit, prenylation of the γ subunit, and myristoylation

294-453: The form of geranylgeranylation. 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. Inhibitors of prenyltransferase enzymes display different specificity for the prenyltransferases, dependent upon the specific compound being utilized. In addition to GTPases,

315-440: The lamin intermediate filaments. The phosphorylated lamin B dimers remain associated with the nuclear membrane via their isoprenyl anchor . Lamin A is targeted to the nuclear membrane by an isoprenyl group but it is cleaved shortly after arriving at the membrane. It stays associated with the membrane through protein-protein interactions of itself and other membrane associated proteins, such as TOR1AIP1 (LAP1). Depolymerization of

336-551: The levels of proteins that have key roles in HR and NHEJ. Mouse cells that are deficient for maturation of prelamin A have increased DNA damage and chromosome aberrations, and show increased sensitivity to DNA damaging agents. In progeria , the inadequacy of DNA repair, due to defective LMNA, may cause features of premature aging (see DNA damage theory of aging ). LMNA has been shown to interact with: Prenylation Prenylation (also known as isoprenylation or lipidation )

357-1013: The nuclear lamins leads to disintegration of the nuclear envelope. Transfection experiments demonstrate that phosphorylation of human lamin A is required for lamin depolymerization, and thus for disassembly of the nuclear envelope, which normally occurs early in mitosis. Mutations in the LMNA gene are associated with several diseases, including Emery–Dreifuss muscular dystrophy , familial partial lipodystrophy , limb girdle muscular dystrophy , dilated cardiomyopathy , Charcot–Marie–Tooth disease , and restrictive dermopathy . A truncated version of lamin A, commonly known as progerin , causes Hutchinson-Gilford-Progeria syndrome . To date over 1,400 SNPs are known [1] . They can manifest in changes on mRNA, splicing or protein (e.g. Arg471Cys, Arg482Gln, Arg527Leu, Arg527Cys, Ala529Val ) level. DNA double-strand damages can be repaired by either homologous recombination (HR) or non-homologous end joining (NHEJ). LMNA promotes genetic stability by maintaining

378-766: 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. 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

399-717: The protein kinase GRK1 also known as rhodopsin kinase (RK) has been shown to undergo farnesylation and carboxyl methylation directed by the carboxyl terminal CVLS CaaX box sequence of the protein. The functional consequence of these post-translational modifications have been shown to play a role in regulating the light-dependent phosphorylation of rhodopsin , a mechanism involved in light adaptation. 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

420-404: The transfer of either a farnesyl or a geranylgeranyl 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 geranylgeranyl transferase I. Farnesylation is a type of prenylation, a post-translational modification of proteins by which an isoprenyl group is added to a cysteine residue. It

441-633: 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 geranylgeranyltransferase, or geranylgeranyltransferase II, transfers (usually) two geranylgeranyl groups to

SECTION 20

#1732883915304
#303696