title: Dimerization of inositol monophosphatase Mycobacterium tuberculosis SuhB is not constitutive, but induced by binding of the activator Mg2+.
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 A 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: School of Biosciences, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. a.k.brown.1@bham.ac.uk
authors.forename: Alistair K
authors.initials: AK
authors.lastname: Brown
authors.forename: Guoyu
authors.initials: G
authors.lastname: Meng
authors.forename: Hemza
authors.initials: H
authors.lastname: Ghadbane
authors.forename: David J
authors.initials: DJ
authors.lastname: Scott
authors.forename: Lynn G
authors.initials: LG
authors.lastname: Dover
authors.forename: Jérôme
authors.initials: J
authors.lastname: Nigou
authors.forename: Gurdyal S
authors.initials: GS
authors.lastname: Besra
authors.forename: Klaus
authors.initials: K
authors.lastname: Fütterer
mesh_terms: D001059:Apoproteins / Q000737:chemistry / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019281:Dimerization; D008274:Magnesium / Q000378:metabolism*; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000145:classification / Q000201:enzymology*; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism
chemical_list: D001059:Apoproteins; D001426:Bacterial Proteins; D021122:Protein Subunits; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase; D008274:Magnesium