Recent advances in protein methylation: Enzymatic methylation of nucleic acid binding proteins

Kim, Sangduk; Park, G. H.; Paik, Woon Ki

doi:10.1007/bf01320895

Cited by 19 publications

(16 citation statements)

References 52 publications

(26 reference statements)

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“…They are catalyzed by protein methylases (11)(12)(13)(14) that specifically recognize the amino acid sequences up-and downstream of the amino acid to be methylated. Since the sequences up-and downstream of the four methylated amino acids in the ␣-subunit of methyl-coenzyme M reductase are very different (2), it has to be concluded that in the post-translational modification four different SAM-dependent protein methylases are involved.…”

Section: Discussionmentioning

confidence: 99%

The Biosynthesis of Methylated Amino Acids in the Active Site Region of Methyl-coenzyme M Reductase

Selmer¹,

Kahnt²,

Goubeaud³

et al. 2000

Journal of Biological Chemistry

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The global production of the greenhouse gas methane by methanogenic archaea reaches 1 billion tons per annum. The final reaction releasing methane is catalyzed by the enzyme methyl-coenzyme M reductase. The crystal structure of methyl-coenzyme M reductase from Methanobacterium thermoautotrophicum revealed the presence of five modified amino acids within the ␣-subunit and near the active site region. Four of these modifications were C-, N-, and S-methylations, two of which, 2-(S)-methylglutamine and 5-(S)-methylarginine, have never been encountered before. We have now confirmed these modifications by mass spectrometry of chymotryptic peptides. With methyl-coenzyme M reductase purified from cells grown in the presence of L-[methyl-D 3 ]methionine, it was shown that the methyl groups of the modified amino acids are derived from the methyl group of methionine rather than from methyl-coenzyme M, an intermediate in methane formation. The D 3 labeling pattern was found to be qualitatively and quantitatively the same as in the two methyl groups of the methanogenic coenzyme F 430 , which are known to be introduced via S-adenosylmethionine. From the results, it is concluded that the methyl groups of the modified amino acids in methyl-coenzyme M reductase are biosynthetically introduced by an S-adenosylmethioninedependent post-translational modification. A mechanism for the methylation of glutamine at C-2 and of arginine at C-5 is discussed.Methyl-coenzyme M reductase catalyzes the final reaction step in the formation of methane by methanogenic archaea. It is a 300-kDa protein composed of three different subunits in an ␣ 2 ␤ 2 ␥ 2 arrangement and contains per mol 2 mol of the nickel porphinoid coenzyme F 430 as prosthetic group (1, 2). The crystal structure of the enzyme from Methanobacterium thermoautotrophicum has recently been solved at 1.45-Å resolution (3). The electron density map suggested the presence of five modified amino acids in the ␣ subunits either at or very near the active site region: 1-N-methylhistidine ␣257 (3-methylhistidine according to IUPAC nomenclature), 5-(S)-methylarginine ␣271, 2-(S)-methylglutamine ␣400, S-methylcysteine ␣452, and thioglycine ␣445, forming a thiopeptide bond (Fig. 1). Thioglycine has been proposed to function as a one-electron relay in the catalytic mechanism (2). Methylation of histidine ␣257, which is involved in substrate binding, probably influences the substrate affinity of the enzyme (3). For the methylation of the three other amino acids, an accidental methylation via methylcoenzyme M-derived methyl radicals has been envisaged. We have now ruled out this possibility by showing that the methyl group of all four methylated amino acids is derived from the methyl group of methionine, most likely via S-adenosylmethionine (SAM).1 Our experiments are based on the previous finding that methionine is taken up from the medium by growing M. thermoautotrophicum and that the methionine taken up is used for protein synthesis and in SAM-dependent methylation reactions rather than in met...

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Section: Discussionmentioning

confidence: 99%

The Biosynthesis of Methylated Amino Acids in the Active Site Region of Methyl-coenzyme M Reductase

Selmer¹,

Kahnt²,

Goubeaud³

et al. 2000

Journal of Biological Chemistry

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“…Protein arginine methylation commonly occurs in arginine-glycine-rich (RG-rich) domains of RNA-binding proteins (Aoki et al, 2002;Christensen and Fuxa, 1988;Cote et al, 2003;Kim et al, 1998;Mears and Rice, 1996;Pelletier et al, 2001;Rho et al, 2001). An eight-member family known as the protein arginine methyltransferases (PRMTs) mediates this post-translational modification.…”

Section: Introductionmentioning

confidence: 99%

Methylation regulates the intracellular protein-protein and protein-RNA interactions of FMRP

Dolzhanskaya¹,

Merz

Aletta

et al. 2006

Journal of Cell Science

103

101

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“…Arginine methylation of nonhistone proteins has been known for nearly four decades, regulating various cellular processes such as transcription and RNA processing, and DNA replication and repair (1,2). However, histone arginine methylation and its role in gene regulation were discovered much more recently (3).…”

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confidence: 99%

Identification of a Novel Inhibitor of Coactivator-associated Arginine Methyltransferase 1 (CARM1)-mediated Methylation of Histone H3 Arg-17

Selvi

Batta

Kishore

et al. 2010

Journal of Biological Chemistry

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Methylation of the arginine residues of histones by methyltransferases has important consequences for chromatin structure and gene regulation; however, the molecular mechanism(s) of methyltransferase regulation is still unclear, as is the biological significance of methylation at particular arginine residues. Here, we report a novel specific inhibitor of coactivator-associated arginine methyltransferase 1 (CARM1; also known as PRMT4) that selectively inhibits methylation at arginine 17 of histone H3 (H3R17). Remarkably, this plant-derived inhibitor, called TBBD (ellagic acid), binds to the substrate (histone) preferentially at the signature motif, "KAPRK," where the proline residue (Pro-16) plays a critical role for interaction and subsequent enzyme inhibition. In a promoter-specific context, inhibition of H3R17 methylation represses expression of p21, a p53-responsive gene, thus implicating a possible role for H3 Arg-17 methylation in tumor suppressor function. These data establish TBBD as a novel specific inhibitor of arginine methylation and demonstrate substrate sequence-directed inhibition of enzyme activity by a small molecule and its physiological consequence.

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Recent advances in protein methylation: Enzymatic methylation of nucleic acid binding proteins

Cited by 19 publications

References 52 publications

The Biosynthesis of Methylated Amino Acids in the Active Site Region of Methyl-coenzyme M Reductase

The Biosynthesis of Methylated Amino Acids in the Active Site Region of Methyl-coenzyme M Reductase

Methylation regulates the intracellular protein-protein and protein-RNA interactions of FMRP

Identification of a Novel Inhibitor of Coactivator-associated Arginine Methyltransferase 1 (CARM1)-mediated Methylation of Histone H3 Arg-17

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