Protein methylation and interaction with the antiproliferative gene, BTG2/TIS21/Pc3

Abstract

The last one and half a decade witnessed an outstanding re-emergence of attention and remarkable progress in the field of protein methylation. In the present article, we describe the early discoveries in research and review the role protein methylation played in the biological function of the antiproliferative gene, BTG2/TIS21/PC3.

Keywords: APRO (antiproliferative) genes; BTG2 (B-cell translocation gene 2); PKMT; PRMT; Protein methylation; TIS21 (TPA-inducible sequences 21); protein methyltransferases.

Fig. 1

Tabulation of publications regarding protein methylation over the thirteen years. The recent dramatic surge in protein methylation research is reflected by increasing publication numbers.

Fig. 2

Protein-lysine methylation. (A) Important chemical structures include ε-N-acetyl-L-lysine and ε-N-methyl-L-lysine, which were studied concomitantly during the early stages of protein methylation research. Conversion of S-adenosyl-L-methionine (AdoMet) to S-adenosyl-L-homocysteine (AdoHcy) results in the transfer of a methyl group to a protein. (B) Sequence of protein-lysine methylation by protein methylase III and protein lysine methyltransferase. The addition of methyl groups to the ε-amine of a lysine residue results in the formation of monomehtyl-, dimehtyl- and trimethyl-lysines.

Fig. 3

Protein-arginine methylation and demethylation and sequences of protein-arginine methylation. The addition of methyl groups to the guanidino nitrogens of arginine residues results in the formation of N^G-monomethyl-, symmetric N^GN'^G-dimethyl- and asymmetric N^GN^G-dimethyl-arginines. Type-I protein arginine methyltransferase (PRMT) in protein methylase-I is active to synthesize N^G-monomethyl-arginine and symmetric N^GN'^G-dimethyl-arginine, and type-II PRMT in protein methylase-I synthesizes N^G-monomethyl-arginine and asymmetric N^GN^G-dimethyl-arginine, indicated in parentheses. However, type III PRMT regulates only N^G-monomethyl-arginine synthesis. Citrulline and methylamine are the products of the deimination of a N^G-monomethyl-arginine residue that is catalyzed by arginine deiminase (PADI). SAM, S-adenosyl-L-methionline; SAH, S-adenosyl-L-homocysteine.

Fig. 4

Protein-lysine demethylation pathways. (A) ε-Alkyllysinase is the first lysine-specific demethylase identified and converts ε-N-monomethyl-lysine to formaldehyde and free lysine by the activity of FAD-dependent amine oxidase (oxygen oxidoreductase). The purified enzyme was named to KDM1A or LSD1. (B) A group of Jumonji C-domain histone demethylase demethylates various ε-N-methylated lysine residues in the presence of Fe⁺⁺ and α-ketoglutarate by the activity of dioxygenase. The reaction generates formaldehyde and free lysine with succinate through decarboxylation and methyl-alcohol intermediate.