Pirin is an iron-dependent redox regulator of NF-κB
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 κB (NF-κB) transcription factor, a critical mediator of intracellular signaling that has been linked to cellular responses to proinflam...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 24; pp. 9722 - 9727 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
11.06.2013
National Acad Sciences |
Subjects | |
Online Access | Get full text |
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Summary: | 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 κB (NF-κB) 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-κB proteins to target κB genes, a finding that suggests that pirin performs a redox-sensing role in NF-κB 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-κB binding that is responsible for modulation of NF-κB’s DNA-binding properties. The nonheme Fe protein pirin is proposed to serve as a reversible functional switch that enables NF-κB to respond to changes in the redox levels of the cell nucleus. |
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Bibliography: | http://dx.doi.org/10.1073/pnas.1221743110 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions: F.L. and A.L. designed research; F.L., I.R., S.E., R.F., L.C., and V.d.S. performed research; S.E. performed site-directed mutagenesis analyses; F.L., I.R., R.F., V.d.S., and A.L. analyzed data; and F.L., I.R., and A.L. wrote the paper. 2Present address: School of Medicine, University of Maryland, Baltimore, MD 21201. Edited by Chuan He, University of Chicago, Chicago, IL, and accepted by the Editorial Board April 19, 2013 (received for review December 12, 2012) 1Present address: Department of Neurology, Emory University, Atlanta, GA 30322. |
ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.1221743110 |