Chemical and biological methods to detect post‐translational modifications of arginine

Abstract

Posttranslational modifications (PTMs) of protein embedded arginines are increasingly being recognized as playing an important role in both prokaryotic and eukaryotic biology, and it is now clear that these PTMs modulate a number of cellular processes including DNA binding, gene transcription, protein-protein interactions, immune system activation, and proteolysis. There are currently four known enzymatic PTMs of arginine ( i.e., citrullination, methylation, phosphorylation, ADP-ribosylation), and two non-enzymatic PTMs (i.e., carbonylation, advanced glycation end-products (AGEs)). Enzymatic modification of arginine is tightly controlled during normal cellular function, and can be drastically altered in response to various second messengers and in different disease states. Non-enzymatic arginine modifications are associated with a loss of metabolite regulation during normal human aging. This abnormally large number of modifications to a single amino acid creates a diverse set of structural perturbations that can lead to altered biological responses. While the biological role of methylation has been the most extensively characterized of the arginine PTMs, recent advances have shown that the once obscure modification known as citrullination is involved in the onset and progression of inflammatory diseases and cancer. This review will highlight the reported arginine PTMs and their methods of detection, with a focus on new chemical methods to detect protein citrullination.

Methods for the Detection of Peptidylarginine Deiminase (PAD) Activity and Protein Citrullination

“…Although the available antibodies display a wide reactivity against citrullinated proteins, some bias for citrulline in a certain amino acid context exists (23), resulting in an incomplete profile of citrullinated proteins present in the sample of interest.…”

Optimizing the Identification of Citrullinated Peptides by Mass Spectrometry: Utilizing the Inability of Trypsin to Cleave after Citrullinated Amino Acids

“…Citrullinated proteins and auto-antibodies against these have been associated with several diseases including: rheumatoid arthritis (RA), Alzheimer's disease, and cancer [6][7][8]. MS remains the only method for identifying the exact site of citrullination, however, the correct identification of citrullinated peptides from MS data by automated search engines remains troublesome [4,9].…”

Chemical and Genetic Approaches to Study Histone Modifications

“…The side-chains of both residues are capable of undergoing methylation to varying degrees. For example, Lys may be mono-, di-, and trimethylated giving rise to three discrete states (Figure 8.4) [93]. Similarly, methylated Arg may exist in any of three different forms: (1) a single methyl group on a sidechain ω-nitrogen (N G -methylarginine, MMA), or, the addition of two methyl groups on either (2) the same nitrogen (ω-N G , N G -asymmetric dimethylarginine, ADMA), or (3) one each on both ω-nitrogens (ω-N G , N' G symmetric dimethylarginine, SDMA) (Figure 8.4).…”