Lysine acetylation of theMycobacterium tuberculosisHU protein modulates its DNA binding and genome organization

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Nucleoid-associated protein HU, a conserved protein across eubacteria is necessary for maintaining the nucleoid organization and global regulation of gene expression.Mycobacterium tuberculosisHU (MtHU) is distinct from the other orthologues having 114 amino acid long carboxyl terminal extensions with a high degree of sequence similarity to eukaryotic histones. In this study, we demonstrate that the DNA binding property of MtHU is regulated by posttranslational modifications akin to eukaryotic histones. MtHU purified fromM. tuberculosiscells is found to be acetylated on multiple lysine residues unlike theE. coliexpressed recombinant protein. Using coimmunoprecipitation assay, we identified Eis as one of the acetyl transferases that interacts with MtHU and modifies it. Although Eis is known to acetylate aminoglycosides, the kinetics of acetylation showed that its protein acetylation activity on MtHU is robust.In vitroEis modified MtHU at various lysine residues, primarily those located at the carboxyl terminal domain. Acetylation of MtHU caused reduced DNA interaction and alteration in DNA compaction ability of the NAP. Over-expression of the Eis leads to hyperacetylation of HU and decompaction of genome. These results provide first insights into the modulation of the nucleoid structure by lysine acetylation in bacteria.

A number of small histone-like DNA binding proteins now known as nucleoid-associated proteins (NAP) organize the bacterial nucleoid. We have identified and characterized acetylation of MtHU, the major NAP in Mycobacterium tuberculosis. We show that MtHU is a substrate for Eis, an acetyltransferase previously known to acetylate aminoglycoside antibiotics. The acetylation of lysine residues of the protein alters its DNA binding and compaction ability to regulate nucleoid organization.

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