Post-translational modifications such as phosphorylation, nitrosylation, and pupylation modulate multiple cellular processes in Mycobacterium tuberculosis. While protein methylation at lysine and arginine residues is widespread in eukaryotes, to date only two methylated proteins in Mtb have been identified. Here, we report the identification of methylation at lysine and/or arginine residues in nine mycobacterial proteins. Among the proteins identified, we chose MtrA, an essential response regulator of a two-component signaling system, which gets methylated on multiple lysine and arginine residues to examine the functional consequences of methylation. While methylation of K207 confers a marginal decrease in the DNA-binding ability of MtrA, methylation of R122 or K204 significantly reduces the interaction with the DNA. Overexpression of S-adenosyl homocysteine hydrolase (SahH), an enzyme that modulates the levels of S-adenosyl methionine in mycobacteria decreases the extent of MtrA methylation. Most importantly, we show that decreased MtrA methylation results in transcriptional activation of mtrA and sahH promoters. Collectively, we identify novel methylated proteins, expand the list of modifications in mycobacteria by adding arginine methylation, and show that methylation regulates MtrA activity. We propose that protein methylation could be a more prevalent modification in mycobacterial proteins.
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Cover Image
Cover Image
The cover image shows a word cloud based on the findings of the review article by Fulcher and Sapkota (pp. 4397–4423) in this issue, depicting the many biological functions and modes of regulation of the CK1 family of Ser/Thr protein kinases. Image created by Luke Fulcher.
Methylation of two-component response regulator MtrA in mycobacteria negatively modulates its DNA binding and transcriptional activation
Anshika Singhal, Richa Virmani, Saba Naz, Gunjan Arora, Mohita Gaur, Parijat Kundu, Andaleeb Sajid, Richa Misra, Ankita Dabla, Suresh Kumar, Jacob Nellissery, Virginie Molle, Ulf Gerth, Anand Swaroop, Kirti Sharma, Vinay K. Nandicoori, Yogendra Singh; Methylation of two-component response regulator MtrA in mycobacteria negatively modulates its DNA binding and transcriptional activation. Biochem J 11 December 2020; 477 (23): 4473–4489. doi: https://doi.org/10.1042/BCJ20200455
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