Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 43, Pages 18177-18182Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0905558106
Keywords
allosteric coupling; allostery; metal sensor protein; metalloregulation; NMR solution structure
Categories
Funding
- National Institutes of Health [GM042569]
- Robert A. Welch Foundation [A-1295]
- Department of Chemistry, Indiana University
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Staphylococcus aureus CzrA is a zinc-dependent transcriptional repressor from the ubiquitous ArsR family of metal sensor proteins. Zn(II) binds to a pair of intersubunit C-terminal alpha 5-sensing sites, some 15 angstrom distant from the DNA-binding interface, and allosterically inhibits DNA binding. This regulation is characterized by a large allosteric coupling free energy (Delta Gc) of approximately +6 kcal mol(-1), the molecular origin of which is poorly understood. Here, we report the solution quaternary structure of homodimeric CzrA bound to a palindromic 28-bp czr operator, a structure that provides an opportunity to compare the two allosteric end states of an ArsR family sensor. Zn(II) binding drives a quaternary structural switch from a closed DNA-binding state to a low affinity open conformation as a result of a dramatic change in the relative orientations of the winged helical DNA binding domains within the dimer. Zn(II) binding also effectively quenches both rapid and intermediate timescale internal motions of apo-CzrA while stabilizing the native state ensemble. In contrast, DNA binding significantly enhances protein motions in the allosteric sites and reduces the stability of the alpha 5 helices as measured by H-D solvent exchange. This study reveals how changes in the global structure and dynamics drive a long-range allosteric response in a large subfamily of bacterial metal sensor proteins, and provides insights on how other structural classes of ArsR sensor proteins may be regulated by metal binding.
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