| Structural highlights
Function
LSR2_MYCTU DNA-bridging protein that has both architectural and regulatory roles. Influences the organization of chromatin and gene expression by binding non-specifically to DNA, with a preference for AT-rich sequences, and bridging distant DNA segments. Represses expression of multiple genes involved in a broad range of cellular processes, including major virulence factors or antibiotic-induced genes, such as iniBAC or efpA. May coordinate global gene regulation and virulence. Also protects mycobacteria against reactive oxygen intermediates during macrophage infection by acting as a physical barrier to DNA degradation.[1] [2] [3] [4]
Publication Abstract from PubMed
Mycobacterium tuberculosis (Mtb) is able to persist in the body through months of multi-drug therapy. Mycobacteria possess a wide range of regulatory proteins, including the protein kinase B (PknB) which controls peptidoglycan biosynthesis during growth. Here, we observed that depletion of PknB resulted in specific transcriptional changes, that are likely caused by reduced phosphorylation of the H-NS-like regulator Lsr2 at threonine 112. The activity of PknB towards this phosphosite was confirmed with purified proteins, and this site was required for adaptation of Mtb to hypoxic conditions, and growth on solid media. Like H-NS, Lsr2 binds DNA in sequence-dependent and non-specific modes. PknB phosphorylation of Lsr2 reduced DNA binding, measured by fluorescence anisotropy and electrophoretic mobility shift assays, and our NMR structure of phosphomimetic T112D Lsr2 suggests that this may be due to increased dynamics of the DNA binding domain. Conversely, the phosphoablative T112A Lsr2 had increased binding to certain DNA sites in ChIP-sequencing, and Mtb containing this variant showed transcriptional changes that correspond with the change in DNA binding. In summary, PknB controls Mtb growth and adaptations to the changing host environment by phosphorylating the global transcriptional regulator Lsr2.
Protein kinase B controls Mycobacterium tuberculosis growth via phosphorylation of the transcriptional regulator Lsr2 at threonine 112.,Alqaseer K, Turapov O, Barthe P, Jagatia H, De Visch A, Roumestand C, Wegrzyn M, Bartek IL, Voskuil MI, O'Hare HM, Ajuh P, Bottrill AR, Witney AA, Cohen-Gonsaud M, Waddell SJ, Mukamolova GV Mol Microbiol. 2019 Sep 28. doi: 10.1111/mmi.14398. PMID:31562654[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Colangeli R, Helb D, Vilcheze C, Hazbon MH, Lee CG, Safi H, Sayers B, Sardone I, Jones MB, Fleischmann RD, Peterson SN, Jacobs WR Jr, Alland D. Transcriptional regulation of multi-drug tolerance and antibiotic-induced responses by the histone-like protein Lsr2 in M. tuberculosis. PLoS Pathog. 2007 Jun;3(6):e87. PMID:17590082 doi:http://dx.doi.org/10.1371/journal.ppat.0030087
- ↑ Chen JM, Ren H, Shaw JE, Wang YJ, Li M, Leung AS, Tran V, Berbenetz NM, Kocincova D, Yip CM, Reyrat JM, Liu J. Lsr2 of Mycobacterium tuberculosis is a DNA-bridging protein. Nucleic Acids Res. 2008 Apr;36(7):2123-35. doi: 10.1093/nar/gkm1162. Epub 2008, Jan 10. PMID:18187505 doi:http://dx.doi.org/10.1093/nar/gkm1162
- ↑ Colangeli R, Haq A, Arcus VL, Summers E, Magliozzo RS, McBride A, Mitra AK, Radjainia M, Khajo A, Jacobs WR Jr, Salgame P, Alland D. The multifunctional histone-like protein Lsr2 protects mycobacteria against reactive oxygen intermediates. Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4414-8. doi:, 10.1073/pnas.0810126106. Epub 2009 Feb 23. PMID:19237572 doi:http://dx.doi.org/10.1073/pnas.0810126106
- ↑ Gordon BR, Li Y, Wang L, Sintsova A, van Bakel H, Tian S, Navarre WW, Xia B, Liu J. Lsr2 is a nucleoid-associated protein that targets AT-rich sequences and virulence genes in Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2010 Jan 20. PMID:20133735
- ↑ Alqaseer K, Turapov O, Barthe P, Jagatia H, De Visch A, Roumestand C, Wegrzyn M, Bartek IL, Voskuil MI, O'Hare HM, Ajuh P, Bottrill AR, Witney AA, Cohen-Gonsaud M, Waddell SJ, Mukamolova GV. Protein kinase B controls Mycobacterium tuberculosis growth via phosphorylation of the transcriptional regulator Lsr2 at threonine 112. Mol Microbiol. 2019 Sep 28. doi: 10.1111/mmi.14398. PMID:31562654 doi:http://dx.doi.org/10.1111/mmi.14398
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