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J. Biol. Chem., Vol. 279, Issue 16, 15752-15762, April 16, 2004
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Kinase by Nitric Oxide Is Induced by the Formation of a Five-coordinate NO-Heme Complex
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From the
Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Sendai 980-8577, Japan, the Center for Integrative Bioscience, Okazaki National Research Institutes, Okazaki 444-8585, Japan, and ¶Institute for Life Support Technology, Yamagata Public Corporation for the Development of Industry, Yamagata 990-2473, Japan
Heme-regulated eukaryotic initiation factor 2
kinase (HRI) regulates the synthesis of hemoglobin in reticulocytes in response to heme availability. HRI contains a tightly bound heme at the N-terminal domain. Earlier reports show that nitric oxide (NO) regulates HRI catalysis. However, the mechanism of this process remains unclear. In the present study, we utilize in vitro kinase assays, optical absorption, electron spin resonance (ESR), and resonance Raman spectra of purified full-length HRI for the first time to elucidate the regulation mechanism of NO. HRI was activated via heme upon NO binding, and the Fe(II)-HRI(NO) complex displayed 5-fold greater eukaryotic initiation factor 2 kinase activity than the Fe(III)-HRI complex. The Fe(III)-HRI complex exhibited a Soret peak at 418 nm and a rhombic ESR signal with g values of 2.49, 2.28, and 1.87, suggesting coordination with Cys as an axial ligand. Interestingly, optical absorption, ESR, and resonance Raman spectra of the Fe(II)-NO complex were characteristic of five-coordinate NO-heme. Spectral findings on the coordination structure of full-length HRI were distinct from those obtained for the isolated N-terminal heme-binding domain. Specifically, six-coordinate NO-Fe(II)-His was observed but not Cys-Fe(III) coordination. It is suggested that significant conformational change(s) in the protein induced by NO binding to the heme lead to HRI activation. We discuss the role of NO and heme in catalysis by HRI, focusing on heme-based sensor proteins.
Received for publication, September 16, 2003 , and in revised form, December 28, 2003.
* This work was supported in part by a grant-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to T. S.) and by the Joint Studies Program (2002–2003) of the Institute for Molecular Science. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
|| To whom correspondence should be addressed: Toru Shimizu, Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan. Tel.: 81-22-217-5604 or -5605; Fax: 81-22-217-5604 or -5390; E-mail: shimizu{at}tagen.tohoku.ac.jp.
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