Protein methylation

Protein methylation is the process through which proteins are modified by enzymes through an addition of methyl groups by S-adenosylmethionine dependent methyltransferases. Methylation of proteins occurs on nitrogen side-chains in arginine and lysine residues and the carboxy-termini of a few different proteins.[1] Before methylation occurs at these termini additional processing may be required. Methylation that occurs on nitrogen atoms in N-terminals is usually unable to be reversed and creates new amino acid residues. Regions of methylated proteins are usually glycine and arginine-rich and are referred to as GAR motifs.[2] These methylations can increase the chemical repertoire of a protein.[3] Methylation is known to have a major effect on the functions of a protein[1] as the S-adenosylmethionine is primarily responsible for activating dependent enzymes called methyltransferases.

Arginine methylation

Arginine methylation is a posttranslational modification; it usually occurs in the nucleus and the main pool of modified proteins have RNA binding properties.[2] Enzymes that facilitate histone acetylation and histones are also arginine methylated. Methylation of arginine residues is catalyzed by at least two different classes of protein arginine methyltransferase enzymes. Type I enzymes catalyze the formation of asymmetric N G,N G-dimethylarginine residues. Type II enzyme catalyzes the formation of symmetric N G,N' G-dimethylarginine residues. Both types generate N G-monomethylarginine intermediates. Arginine methylation affects the interactions between proteins and has been implicated in a variety of cellular processes, including protein trafficking, signal transduction and transcriptional regulation.[2]

Lysine methylation

Lysine methylation plays a central part in the way that histones interact with proteins. Most lysine methyltransferases contain an evolutionarily conserved SET domain. SET domains possess S-adenosylmethionine-dependent methyltransferase activity, but are structurally distinct from other S-adenosylmethionine binding proteins.[4] Lysine residues accept up to three methyl groups forming mono-, di-and trimethylated derivatives.

Different SET domain-containing proteins possess distinct substrate specificities. For example, SET1, SET7 and MLL methylate lysine 4 of histone H3, whereas Suv39h1, ESET and G9a specifically methylate lysine 9 of histone H3. Methylation at lysine 4 and lysine 9 are mutually exclusive and the consequences of site-specific methylation are diametrically opposed. Methylation at lysine 4 correlates with an active state of transcription. Methylation at lysine 9 is associated with transcriptional repression and heterochromatin. Other lysine residues on histone H3 and histone H4 are also significant sites of methylation by specific SET domain-containing enzymes. Although the histones are the prime target of lysine methyltransferases, other cellular proteins carry N-methyllysine residues including elongation factor 1A and the calcium sensing protein calmodulin.[4]

Prenylcysteine methylation

Eukaryotic proteins with C-termini that end in a CAAX motif are often subjected to a series of posttranslational modifications. This CAAX-tail processing takes place in three steps. First, a prenyl lipid anchor is attached to the cysteine through a thioester linkage. Then endoproteolysis occurs to remove the last three amino acids of the protein to expose the prenylcysteine α-COOH group. Finally, the exposed prenylcysteine group is methylated. The importance of this modification can be seen in targeted disruption of the methyltransferase for mouse CAAX proteins, when isoprenylcysteine carboxyl methyltransferase, resulted in mid-gestation lethality.[5]

The biological function of prenylcysteine methylation is to facilitate the targeting of CAAX proteins to membrane surfaces within cells. Prenylcysteine can be demethylated and this reverse reaction is catalyzed by isoprenylcysteine carboxyl methylesterases. CAAX box containing proteins that are prenylcysteine methylated include Ras, GTP-binding proteins, nuclear lamins and certain protein kinases. Many of these proteins participate in cell signaling, and they utilize prenylcysteine methylation to concentrate them on the cytosolic surface of the plasma membrane where they are functional.[5]

Protein phosphatase 2A methylation

In eukaryotic cells, phosphatases catalyze the removal of phosphate groups from tyrosine, serine and threonine phosphoproteins. The catalytic subunit of the major serine/threonine phosphatases, is covalently modified by the reversible methylation of its C-terminus to form a leucine carboxy methyl ester. Unlike CAAX motif methylation, no C-terminal processing is required to facilitate methylation. This C-terminal methylation event regulates the recruitment of regulatory proteins into complexes through the stimulation of protein–protein interactions, thus indirectly regulating the activity of the serine-threonine phosphatases complex.[6] Methylation is catalyzed by a unique protein phosphatase methyltransferase. The methyl group is removed by a specific protein phosphatase methylesterase. These two opposed enzymes make serine-threonine phosphatases methylation a dynamic process in response to stimuli.[6]

L-isoaspartyl methylation

Damaged proteins accumulate isoaspartyl which causes protein instability, loss of biological activity and stimulation of autoimmune responses. A methyltransferase dependent pathway exists for the conversion of L-isoaspartyl back to l-aspartyl. The spontaneous age-dependent degradation of l-aspartyl residue results in the formation of a succinimidyl intermediate. This intermediate is spontaneously hydrolyzed either back to l-aspartyl or, in a more favorable reaction, to abnormal L-isoaspartyl. To prevent the accumulation of L-isoaspartyl, this residue is methylated by the protein L-isoaspartyl O-methyltransferase, which catalyzes the formation of a methyl ester, which in turn is converted back to a succinimidyl intermediate.[7] Loss and gain of function mutations have unmasked the biological importance of protein L-isoaspartyl O-methyltransferase in age-related processes. Mice lacking this enzyme die young as a result of fatal epilepsy, whereas flies engineered to over-express protein L-isoaspartyl O-methyltransferase exhibit an increase in life span of over 30%.[7]

Physical effect of protein methylation

A common theme with methylated proteins, as is also the case with phosphorylated proteins, is the role this modification plays in the regulation of protein–protein interactions. The arginine methylation of proteins can either inhibit or promote protein–protein interactions depending on the type of methylation. The asymmetric dimethylation of arginine residues in close proximity to proline-rich motifs can inhibit the binding to SH3 domains.[8] The opposite effect is seen with interactions between the survival of motor neurons protein and the snRNP proteins SmD1, SmD3 and SmB/B', where binding is promoted by symmetric dimethylation of arginine residues in the snRNP proteins.[9] A well-characterized example of a methylation dependent protein–protein interaction is related to the selective methylation of lysine 9, by Suv39h1 on the N-terminal tail of the histone H3.[4] Di- and tri-methylation of this lysine residue facilitates the binding of heterochromatin protein HP1. Because HP1 and Suv39h1 interact, it is thought the binding of HP1 to histone H3 is maintained and even allowed that to spread along the chromatin. The HP1 protein harbors a Chromo domain that is responsible for the methyl-dependent interaction between HP1 and lysine 9 of histone H3. It is likely that additional Chromo domain-containing proteins will bind the same site as HP1, as well as to other lysine methylated positions on histones H3 and H4. C-terminal methylation has also been implicated in the regulation of protein–protein interactions. The methylation of the protein phosphatases 2A catalytic subunit enhances the binding of the regulatory B subunit and facilitates holoenzyme assembly.[6]

References

  1. 1 2 Schubert, H.; Blumenthal, R.; Cheng, X. (2007). "1 Protein methyltransferases: Their distribution among the five structural classes of adomet-dependent methyltransferases 1". The Enzymes. 24: 3–22. doi:10.1016/S1874-6047(06)80003-X.
  2. 1 2 3 McBride, A.; Silver, P. (2001). "State of the Arg: Protein Methylation at Arginine Comes of Age". Cell. 106 (1): 5–8. doi:10.1016/S0092-8674(01)00423-8. PMID 11461695.
  3. ↑ Clarke, S (1993). "Protein methylation". Curr. Opin. Cell Biol. 5: 977–83. PMID 8129951.
  4. 1 2 3 Kouzarides, T (2002). "Histone methylation in transcriptional control". Current Opinion in Genetics & Development. 12 (2): 198–209. doi:10.1016/S0959-437X(02)00287-3. PMID 11893494.
  5. 1 2 Bergo, M (2000). "Isoprenylcysteine Carboxyl Methyltransferase Deficiency in Mice". Journal of Biological Chemistry. 276: 5841–5845. doi:10.1074/jbc.c000831200.
  6. 1 2 3 TTolstykh, T (2000). "Carboxyl methylation regulates phosphoprotein phosphatase 2A by controlling the association of regulatory B subunits". The EMBO Journal. 19 (21): 5682–5691. doi:10.1093/emboj/19.21.5682. PMC 305779Freely accessible. PMID 11060019.
  7. 1 2 Clarke, S (2003). "Aging as war between chemical and biochemical processes: Protein methylation and the recognition of age-damaged proteins for repair". Ageing Research Reviews. 2 (3): 263–285. doi:10.1016/S1568-1637(03)00011-4.
  8. ↑ Bedford, M (2000). "Arginine Methylation Inhibits the Binding of Proline-rich Ligands to Src Homology 3, but Not WW, Domains". Journal of Biological Chemistry. 275: 16030–16036. doi:10.1074/jbc.m909368199.
  9. ↑ Friesen, W.; Massenet, S.; Paushkin, S.; Wyce, A.; Dreyfuss, G. (2001). "SMN, the Product of the Spinal Muscular Atrophy Gene, Binds Preferentially to Dimethylarginine-Containing Protein Targets". Molecular Cell. 7 (5): 1111–1117. doi:10.1016/S1097-2765(01)00244-1. PMID 11389857.
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