The six zinc fingers of metal-responsive element-binding transcription factor-1 form stable and quasi-ordered structures with relatively small differences in zinc affinities

doi:10.1074/jbc.M505217200

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A more recent version of this article appeared on August 5, 2005 Originally published In Press as doi:10.1074/jbc.M505217200 on June 4, 2005

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Papers In Press, published online ahead of print May 31, 2005
J. Biol. Chem, 10.1074/jbc.M505217200
Submitted on May 11, 2005
Accepted on May 31, 2005

The six zinc fingers of metal-responsive element-binding transcription factor-1 form stable and quasi-ordered structures with relatively small differences in zinc affinities

Belinda M. Potter, Linda S. Feng, Priya Parasuram, Viktor A. Matskevich, Jed A. Wilson, Glen K. Andrews, and John H. Laity

Division of Cell Biology and Biophysics, School of Biological Sciences, University of Missouri-Kansas City, Kansas CIty, MO 64110

Corresponding Author: laityj{at}umkc.edu

Six Cys₂His₂ zinc fingers (F1-6) comprise the DNA binding domain of metal-responsive element-binding transcription factor-1 (MTF-1). F1-6 is necessary for basal and zinc-induced expression of metallothionein genes. Analysis of NMR structural and dynamic data for an F1-6 protein construct demonstrates that each zinc finger adopts a stable $beta$ $beta$ $alpha$ fold in the presence of stoichiometric Zn(II) provided that all cysteine ligands are in a reduced state. Parallel studies of protein constructs spanning the four N-terminal core DNA binding fingers (F1-4) and two C-terminal low DNA affinity fingers (F5-6) reveal similar stable zinc finger structures. In both the F1-6 and F5-6 proteins, the finger 5 cysteines were found to readily oxidize at neutral pH. Detailed spectral density and hydrodynamic analysis of ¹⁵N-relaxation data reveal quasi-ordered anisotropic rotational diffusion properties of the six F1-6 zinc fingers, which could influence MTF-1 DNA binding and metal-sensing functions. A more general effect on the rotational diffusion properties of Cys₂His₂ zinc fingers is also uncovered that is dependent upon the position of each finger within multi-finger domains. Analysis of NMR ¹H-¹⁵N-HSQC spectral peak intensities measured as a function of added Zn(II) in conjunction with Zn(II) binding modeling studies indicate that the Zn(II) affinities of all MTF-1 zinc fingers are within approximately 10-50-fold. These analyses further suggest that metal-sensing by MTF-1 in eukaryotic cells involves multiple zinc fingers and occurs over a 100-fold or less range of accessible Zn(II) concentration.

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