SUMOylation of histone like DNA binding protein of <i>Helicobacter pylori</i> (Hup) hinted by sequence analysis and molecular docking studies: A preliminary investigation based on homology modelled Hup structures
Creators: name: Kumar, Dinesh
Publisher: name: F1000 Research Limited
Year: 2017

description: <i>Helicobacter pylori</i> (<i>H. pylori</i>) –the human gastric pathogen- is a paradigm for chronic bacterial infections in humans and infects approximately more than 50% of the world's human population. The bacterium express a Histone-like DNA binding protein encoded by the gene hup, which is homolog to the <i>Escherichia coli</i> histone-like protein HU.<sup>1</sup> The protein –referred here as Hup- is one of the abundant nucleoid-associated proteins in the bacterial chromatin and plays an important role in maintenance of chromosomal architecture, stabilizing higher-order nucleoprotein complexes and in global regulation of DNA transactions.<sup>2,3</sup> The protein is named as histone-like, not because of sequence or structural similarity to eukaryotic histones, but because of comparable physiochemical properties, roles in nucleoid compaction and additional Lysine rich sequence like eukaryotic histone H1.<sup>4</sup> Structurally, Hup is a small 94 amino acid positively charged basic protein which predominantly exists as a homodimer in solution and binds without sequence specificity to duplex DNA, but recognizes DNA repair intermediates with high affinity.<sup>1,5</sup> Studies showed that it also plays an important role in protecting <i>H. pylori</i> genomic DNA from damage elicited by acidic/oxidative stress conditions that the bacterium commonly encounters in the host.<sup>1,5</sup><br><br>Infection with <i>H. pylori</i> represents a key factor in the etiology of various gastrointestinal diseases, ranging from chronic active gastritis to duodenal/peptic ulcers and gastric cancer.<sup>6,7</sup> Disease outcome is the result of the complex interplay between the host and the pathogen which can be explained in part by studying the interaction of human proteins with the proteins or virulence factor secreted <i>in vitro</i> by <i>H. pylori</i>.<sup>8,9</sup> The <i>in vitro</i> secreted proteins contribute to gastric inflammation and epithelial damage (by toxin release); thus aid bacterial invasion in host tissue. Additionally, these proteins –through interacting with host proteins and altering their activities- may provide a mechanism for the bacteria to survive within host system against its immunological defense system. As Hup is also secreted <i>in vitro</i> by <i>H. pylori</i>,<sup>8</sup> thus it may have its role in disease pathogenesis through dysregulating host metabolic pathways or modulating immune system. This is possible only if <i>H. pylori</i> Hup interacts with some human proteins. Among various proteins in humans, small ubiquitin-like modifier proteins (SUMOs) act to change the function of target proteins through their interaction or post-translational modifications.<sup>10,11</sup> The process known as SUMOylation has also been implicated in the regulation of transcription and the maintenance of genome stability.<sup>12</sup> Further, it is known to promote an efficient immune response to combat pathogenic infections through regulating various innate immune pathways.<sup>13,14</sup> For SUMOylation, SUMOs identify their substrates through specific binding motifs –known as SUMO binding motifs (SBMs) exposed on the surface of target protein. The most commonly identified ones are B-K-X-E<sup>10</sup> and B-X-B-B<sup>11,15</sup> (where K is lysine, E is glutamate, X is any residue,  and B represent a large hydrophobic amino acid, most commonly valine, leucine or isoleucine). A careful analysis of amino acid sequence of Hup and those of some other related HU proteins revealed the presence of two closely similar and conserved SBMs (see Figure 1 in the poster). Additionally, the SUMO proteins epitomize negatively charged surface which confers them the ability to bind to DNA/RNA binding proteins. Based on the presence of both SBMs and negatively charged surface, it is legitimate to consider that SUMO proteins would bind to DNA binding HU proteins such as <i>H. pylori</i> Hup as envisaged and computationally demonstrated here using molecular docking. Future experimental studies are however imperative to prove this envisaged interaction between <i>H. pylori</i> Hup and human SUMO proteins and its relevance in the context of disease pathogenesis.  <br> <br>References:<br> <br>(1)     Wang, G.; Lo, L. F.; Maier, R. J. 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