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Molecular and Cellular Biology, August 2008, p. 4697-4711, Vol. 28, No. 15
0270-7306/08/$08.00+0     doi:10.1128/MCB.00236-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

A Novel Heme-Regulatory Motif Mediates Heme-Dependent Degradation of the Circadian Factor Period 2 ^,

Jianhua Yang,¹ Kevin D. Kim,¹ Andrew Lucas,¹ Karen E. Drahos,¹ Carlo S. Santos,¹ Sean P. Mury,¹ Daniel G. S. Capelluto,² and Carla V. Finkielstein^1*

Department of Biological Sciences,¹ Department of Chemistry, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061²

Received 12 February 2008/ Returned for modification 13 March 2008/ Accepted 17 May 2008

Although efforts have been made to identify circadian-controlled genes regulating cell cycle progression and cell death, little is known about the metabolic signals modulating circadian regulation of gene expression. We identify heme, an iron-containing prosthetic group, as a regulatory ligand controlling human Period-2 (hPer2) stability. Furthermore, we define a novel heme-regulatory motif within the C terminus of hPer2 (SC⁸⁴¹PA) as necessary for heme binding and protein destabilization. Spectroscopy reveals that whereas the PAS domain binds to both the ferric and ferrous forms of heme, SC⁸⁴¹PA binds exclusively to ferric heme, thus acting as a redox sensor. Consequently, binding prevents hPer2 from interacting with its stabilizing counterpart cryptochrome. In vivo, hPer2 downregulation is suppressed by inhibitors of heme synthesis or proteasome activity, while SA⁸⁴¹PA is sufficient to stabilize hPer2 in transfected cells. Moreover, heme binding to the SC⁸⁴¹PA motif directly impacts circadian gene expression, resulting in altered period length. Overall, the data support a model where heme-mediated oxidation triggers hPer2 degradation, thus controlling heterodimerization and ultimately gene transcription.

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* Corresponding author. Mailing address: Department of Biological Sciences, Virginia Polytechnic Institute and State University, 2119 Derring Hall, Blacksburg, VA 24061. Phone: (540) 231-1159. Fax: (540) 231-9307. E-mail: finkielc{at}vt.edu

Published ahead of print on 27 May 2008.

Supplemental material for this article may be found at http://mcb.asm.org/.

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Molecular and Cellular Biology, August 2008, p. 4697-4711, Vol. 28, No. 15
0270-7306/08/$08.00+0     doi:10.1128/MCB.00236-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.