Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 24, Pages 9722-9727Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1221743110
Keywords
metalloprotein; coregulator; reactive oxygen species (ROS); oxidative stress; signal transduction activation
Categories
Funding
- US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]
- Georgia Cancer Coalition Distinguished Cancer Scholar Program
- National Science Foundation [MCB-0843537]
- Georgia State University fellowship
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [0843537] Funding Source: National Science Foundation
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Pirin is a nuclear nonheme Fe protein of unknown function present in all human tissues. Here we describe that pirin may act as a redox sensor for the nuclear factor kappa B ( NF-kappa B) transcription factor, a critical mediator of intracellular signaling that has been linked to cellular responses to proinflammatory signals and controls the expression of a vast array of genes involved in immune and stress responses. Pirin's regulatory effect was tested with several metals and at different oxidations states, and our spectroscopic results show that only the ferric form of pirin substantially facilitates binding of NF kappa B proteins to target kappa B genes, a finding that suggests that pirin performs a redox-sensing role in NF-kappa B regulation. The molecular mechanism of such a metal identity- and redox state-dependent regulation is revealed by our structural studies of pirin. The ferrous and ferric pirin proteins differ only by one electron, yet they have distinct conformations. The Fe center is shown to play an allosteric role on an R-shaped surface area that has two distinct conformations based on the identity and the formal redox state of the metal. We show that the R-shaped area composes the interface for pirin NF-kappa B binding that is responsible for modulation of NF-kappa B's DNA-binding properties. The nonheme Fe protein pirin is proposed to serve as a reversible functional switch that enables NF-kappa B to respond to changes in the redox levels of the cell nucleus.
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