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J. Biol. Chem., Vol. 281, Issue 42, 31553-31561, October 20, 2006

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The First Structure from the SOUL/HBP Family of Heme-binding Proteins, Murine P22HBP^*

Jorge S. Dias, Anjos L. Macedo, Gloria C. Ferreira, Francis C. Peterson^¶, Brian F. Volkman^¶, and Brian J. Goodfellow^||1

From the Rede de Química e Tecnologia, Centro de Química Fina e Biotecnologia, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal, the Department of Molecular Medicine, College of Medicine, University of South Florida, Tampa, Florida 33612-4799, the ^¶Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, and ^||Centro de Investigação em Materiais Cerâmicos e Compósitos, Departamento de Química, Universidade de Aveiro, 3810-193 Aveiro, Portugal

Murine p22HBP, a 22-kDa monomer originally identified as a cytosolic heme-binding protein ubiquitously expressed in various tissues, has 27% sequence identity to murine SOUL, a heme-binding hexamer specifically expressed in the retina. In contrast to murine SOUL, which binds one heme per subunit via coordination of the Fe(III)-heme to a histidine, murine p22HBP binds one heme molecule per subunit with no specific axial ligand coordination of the Fe(III)-heme. Using intrinsic protein fluorescence quenching, the values for the dissociation constants of p22HBP for hemin and protoporphyrin-IX were determined to be in the low nanomolar range. The three-dimensional structure of murine p22HBP, the first for a protein from the SOUL/HBP family, was determined by NMR methods to consist of a 9-stranded distorted -barrel flanked by two long -helices. Although homologous domains have been found in three bacterial proteins, two of which are transcription factors, the fold determined for p22HBP corresponds to a novel plus fold in a eukaryotic protein. Chemical shift mapping localized the tetrapyrrole binding site to a hydrophobic cleft formed by residues from helix _A and an extended loop. In an attempt to assess the structural basis for tetrapyrrole binding in the SOUL/HBP family, models for the p22HBP-protoporphyrin-IX complex and the SOUL protein were generated by manual docking and automated methods.

Received for publication, June 22, 2006 , and in revised form, August 10, 2006.

The atomic coordinates and structure factors (code 2GOV) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by the Fundação para a Ciência e Tecnologia, Programa Operacional Ciência, Tecnologia, Inovação (POCTI), and Fundo Europeu de Desenvolvimento Regional in Portugal (Grant SFRH/BD/3091/2000 to J. S. D. and Grant POCTI/BME/39184/2001 to B. J. G. and A. L. M.) and National Institutes of Health Grants GM64598 (to B. F. V.) and DK63191 (to G. C. F.). 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.

¹ To whom correspondence should be addressed. Tel.: 351-234-401-506; Fax: 351-234-370-084; E-mail: brian.goodfellow{at}dq.ua.pt.

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