Tetramerization at Low pH Licenses DNA Methylation Activity of M.HpyAXI in the Presence of Acid Stress

• Published in: Journal of molecular biology 2020-01, Vol.432 (2), p.324-342
• Main Authors: Narayanan, Naveen, Banerjee, Arun, Jain, Deepti, Kulkarni, Dhananjaya S., Sharma, Rahul, Nirwal, Shivlee, Rao, Desirazu N., Nair, Deepak T.
• Format: Article
• Language: English
• Subjects: Acid stress; DNA methyltransferase; Helicobacter pylori; pH sensitive; Tetramer
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2019.10.001

Methylation of genomic DNA can influence the transcription profile of an organism and may generate phenotypic diversity for rapid adaptation in a dynamic environment. M.HpyAXI is a Type III DNA methyltransferase present in Helicobacter pylori and is upregulated at low pH. This enzyme may alter the expression of critical genes to ensure the survival of this pathogen at low pH inside the human stomach. M.HpyAXI methylates the adenine in the target sequence (5′-GCAG-3′) and shows maximal activity at pH 5.5. Type III DNA methyltransferases are found to form an inverted dimer in the functional form. We observe that M.HpyAXI forms a nonfunctional dimer at pH 8.0 that is incapable of DNA binding and methylation activity. However, at pH 5.5, two such dimers associate to form a tetramer that now includes two functional dimers that can bind and methylate the target DNA sequence. Overall, we observe that the pH-dependent tetramerization of M.HpyAXI ensures that the enzyme is licensed to act only in the presence of acid stress. [Display omitted] •DNA MTase M.HpyAXI from H. pylori is only active in acidic conditions.•M.HpyAXI exists as an inactive dimer in alkaline pH.•At acidic pH, M.HpyAXI forms a tetramer with two active sites.•H232 residue plays an important role in pH-induced tetramerization.•Low pH-induced activation mechanism could be used to engineer pH-sensitive MTase.