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Non-histone protein methylation as a regulator of cellular signalling and function

Nature Reviews Molecular Cell Biology volume 16, pages 5–17 (2015)Cite this article

Subjects

Key Points

  • Approximately 4,000 Lys and Arg methylation sites have been identified in human proteins to date, most of which are on non-histone proteins.

  • The mapping of methyltransferase–substrate networks indicated that a large array of cellular functions is regulated by protein methylation, ranging from chromatin structure remodelling to gene transcription, DNA repair, protein synthesis, RNA metabolism, cell cycle progression, apoptosis and signal transduction.

  • Crosstalk often occurs between phosphorylation and methylation, and between two neighbouring methylated residues. This may result in the enhancement or repression of protein function and cellular processes.

  • Methylation has emerged as an important modulator of cell signalling. Lys or Arg methylation of regulatory proteins in the MAPK, WNT, BMP, Hippo and JAK–STAT signalling pathways were shown to modulate signalling sensitivity, strength, or duration.

  • Methylation signals on histone and non-histone proteins may regulate each other to affect nuclear processes. Proteins that contain a methyl-lysine- or methylarginine-binding domain often function as hubs of signalling integration or diversification. Examples are found in the regulation of nuclear factor-κB and p53 transcriptional activity by methylation.

  • The size of the methylproteome may be as large as that of the tyrosine phosphoproteome. Advances in mass spectrometry and related technologies are speeding up the characterization of the methylproteome and the elucidation of its functions in health and disease.

Abstract

Methylation of Lys and Arg residues on non-histone proteins has emerged as a prevalent post-translational modification and as an important regulator of cellular signal transduction mediated by the MAPK, WNT, BMP, Hippo and JAK–STAT signalling pathways. Crosstalk between methylation and other types of post-translational modifications, and between histone and non-histone protein methylation frequently occurs and affects cellular functions such as chromatin remodelling, gene transcription, protein synthesis, signal transduction and DNA repair. With recent advances in proteomic techniques, in particular mass spectrometry, the stage is now set to decode the methylproteome and define its functions in health and disease.

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Figure 1: Lys and Arg methylation.
Figure 2: Methyltransferase–substrate networks.
Figure 3: Regulation of protein function by PTM crosstalk.
Figure 4: Regulation of cellular signalling pathways by protein methylation.
Figure 5: Integration of histone and non-histone protein methylation signals in DNA double-strand break repair.

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Acknowledgements

The authors apologize to those whose findings are relevant to this Review but could not be cited owing to space constraints. Work in the laboratory of S.S.-C.L. is supported by grants from the Canadian Cancer Society, the Ontario Research Fund (ORF) and the Canadian Institute of Health Research. K.K.B. is the recipient of a Natural Science and Engineering Council of Canada (NSERC) Postdoctoral Fellowship. S.S.-C.L. holds a Canada Research Chair in Functional Genomics and Cellular Proteomics.

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  1. Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, N6A 5C1, Ontario, Canada

    Kyle K. Biggar & Shawn S.-C. Li

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  1. Kyle K. Biggar
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Correspondence to Shawn S.-C. Li.

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Supplementary information

Supplementary information S1 (table)

Non-histone Lys methylation (DOC 225 kb)

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Glossary

S-Adenosylmethionine

The methyl donor in numerous methylation reactions, including Lys and Arg methylation. It is generated by methionine adenosyltransferase from ATP and methionine.

Tudor domains

Modular methyl-binding domains that were originally identified in the Tudor protein of Drosophila melanogaster. The Tudor domains often exist in multiple copies in a protein, and they can bind methylated Lys or methylated Arg.

Chromodomain

A modular methyl-binding domain of 40–50 amino acids that is commonly found in proteins involved in chromatin remodelling.

MBT

The malignant brain tumour (MBT) domain is a protein module implicated in the binding of methylated histone tails. MBT domains are found in a number of nuclear proteins that are involved in transcriptional regulation.

Gly–Arg-rich motif

(GAR Motif). A motif (RGG/RG) thought to be involved in nucleic acid binding. The Arg residue within the motif is frequently methylated by protein Arg methyltransferases.

SRC homology 2 domain

(SH2 domain). A modular domain of ∼100 amino acids that binds specifically to phosphotyrosine-containing peptides or proteins. Human cells express 120 different SH2 domains, many of which are involved in regulating tyrosine kinase function and signal transduction.

Modular domains

Conserved parts of a protein sequence or structure that confer a particular function. These domains can also remain functional independent of the parent protein.

Multiple reaction monitoring

(MRM; also known as selective reaction monitoring (SRM)). This is a highly sensitive mass spectrometry method for the targeted quantification of proteins and peptides in complex biological samples. It monitors only specific product ions from a precursor ion (peptide), while filtering out other peptides.

Methyl-SILAC

A mass spectroscopy-based method for identifying and quantifying changes in Lys or Arg methylation using stable isotope labelling by amino acids in cell culture (SILAC). Cells are cultured with [13CD3]methionine, which is then converted to [13CD3]SAM and incorporated in vivo into methylation sites. The labelling of methylation sites by the heavy 13CD3-methyl group facilitates their identification and quantification by mass spectrometry.

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Biggar, K., Li, SC. Non-histone protein methylation as a regulator of cellular signalling and function. Nat Rev Mol Cell Biol 16, 5–17 (2015). https://doi.org/10.1038/nrm3915

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