Dimerization of inositol monophosphatase Mycobacterium tuberculosis SuhB is not constitutive, but induced by binding of the activator Mg2+

Brown, A.K.; Meng, G.; Ghadbane, H.; Scott, D.J.; Dover, L.G.; Nigou, J.; Besra, G.S.; Fütterer, K.

Abstract

Background The cell wall of Mycobacterium tuberculosis contains a wide range of phosphatidyl inositol-based glycolipids that play critical structural roles and, in part, govern pathogen-host interactions. Synthesis of phosphatidyl inositol is dependent on free myo-inositol, generated through dephosphorylation of myo-inositol-1-phosphate by inositol monophosphatase (IMPase). Human IMPase, the putative target of lithium therapy, has been studied extensively, but the function of four IMPase-like genes in M. tuberculosis is unclear. Results We determined the crystal structure, to 2.6 Å resolution, of the IMPase M. tuberculosis SuhB in the apo form, and analysed self-assembly by analytical ultracentrifugation. Contrary to the paradigm of constitutive dimerization of IMPases, SuhB is predominantly monomeric in the absence of the physiological activator Mg2+, in spite of a conserved fold and apparent dimerization in the crystal. However, Mg2+ concentrations that result in enzymatic activation of SuhB decisively promote dimerization, with the inhibitor Li+ amplifying the effect of Mg2+, but failing to induce dimerization on its own. Conclusion The correlation of Mg2+-driven enzymatic activity with dimerization suggests that catalytic activity is linked to the dimer form. Current models of lithium inhibition of IMPases posit that Li+ competes for one of three catalytic Mg2+ sites in the active site, stabilized by a mobile loop at the dimer interface. Our data suggest that Mg2+/Li+-induced ordering of this loop may promote dimerization by expanding the dimer interface of SuhB. The dynamic nature of the monomer-dimer equilibrium may also explain the extended concentration range over which Mg2+ maintains SuhB activity.

Citation

Brown, A., Meng, G., Ghadbane, H., Scott, D., Dover, L., Nigou, J., …Fütterer, K. (2007). Dimerization of inositol monophosphatase Mycobacterium tuberculosis SuhB is not constitutive, but induced by binding of the activator Mg2+. BMC structural biology, 7, Article 55. https://doi.org/10.1186/1472-6807-7-55

• Journal Article Type: Article
• Acceptance Date: Aug 28, 2007
• Online Publication Date: Aug 28, 2007
• Publication Date: Aug 28, 2007
• Deposit Date: Oct 6, 2015
• Publicly Available Date: Dec 8, 2017
• Journal: BMC Structural Biology
• Publisher: BioMed Central
• Peer Reviewed: Peer Reviewed
• Volume: 7
• Article Number: 55
• DOI: https://doi.org/10.1186/1472-6807-7-55
• Public URL: https://durham-repository.worktribe.com/output/1401373