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Metal-linked dimerization in the iron-dependent regulator from Mycobacterium tuberculosis
Mariya Semavina1, Dorothy Beckett, Timothy M Logan
1Graduate Program in Molecular Biophysics, Florida State University, Tallahassee, Florida 32306, USA.
Biochemistry
|October 13, 2006
Summary
The iron-dependent regulator (IdeR) protein in Mycobacterium tuberculosis binds metals cooperatively, with dimerization significantly contributing to this process. This coupling influences IdeR
Area of Science:
- Biochemistry
- Molecular Biology
- Microbiology
Background:
- The iron-dependent regulator (IdeR) controls iron homeostasis, oxidative stress, and virulence in Mycobacterium tuberculosis.
- IdeR is activated by various divalent metal ions, including Fe(II), Ni(II), Co(II), Cd(II), Mn(II), and Zn(II).
- Metal-induced protein activation involves complex conformational changes and homodimerization.
Purpose of the Study:
- To investigate the energetics of dimerization and metal binding in IdeR.
- To elucidate the relationship between metal binding and IdeR homodimerization.
- To understand the constraints on IdeR activation mechanisms.
Main Methods:
- Equilibrium analytical ultracentrifugation to determine dimerization energetics.
- Fluorescence spectroscopy to monitor metal-induced conformational changes.
- Equilibrium dialysis to quantitatively measure metal binding affinity.
Main Results:
- Apo-IdeR dimer dissociation constant was 4.0 microM, decreasing significantly upon Ni(II) binding.
- Ni(II) binding induced concentration-dependent changes in tryptophan fluorescence.
- IdeR exhibited strongly positive cooperative metal binding (3 equivalents/monomer, Kd = 2.2 microM, Hill coefficient = 2).
- Metal binding was non-cooperative in an IdeR variant with reduced dimerization affinity.
Conclusions:
- Dimerization is a key factor driving the positive cooperative metal binding of IdeR.
- The strong coupling between metal binding and dimerization imposes specific constraints on IdeR activation.
- Understanding these interactions is crucial for deciphering IdeR's regulatory role in M. tuberculosis.
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