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J. Biol. Chem., Vol. 282, Issue 51, 37112-37123, December 21, 2007

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The Active Site of an Algal Prolyl 4-Hydroxylase Has a Large Structural Plasticity^*

M. Kristian Koski, Reija Hieta, Claudia Böllner, Kari I. Kivirikko, Johanna Myllyharju, and Rik K. Wierenga¹

From the Biocenter Oulu and Department of Biochemistry and Collagen Research Unit, Biocenter Oulu and Department of Medical Biochemistry and Molecular Biology, University of Oulu, FIN-90014 Oulu, Finland

Prolyl 4-hydroxylases (P4Hs) are 2-oxoglutarate dioxygenases that catalyze the hydroxylation of peptidyl prolines. They play an important role in collagen synthesis, oxygen homeostasis, and plant cell wall formation. We describe four structures of a P4H from the green alga Chlamydomonas reinhardtii, two of the apoenzyme at 1.93 and 2.90Å resolution, one complexed with the competitive inhibitor Zn²⁺, and one with Zn²⁺ and pyridine 2,4-dicarboxylate (which is an analogue of 2-oxoglutarate) at 1.85Å resolution. The structures reveal the double-stranded β-helix core fold (jellyroll motif), typical for 2-oxoglutarate dioxygenases. The catalytic site is at the center of an extended shallow groove lined by two flexible loops. Mutagenesis studies together with the crystallographic data indicate that this groove participates in the binding of the proline-rich peptide-substrates. It is discussed that the algal P4H and the catalytic domain of collagen P4Hs have notable structural similarities, suggesting that these enzymes form a separate structural subgroup of P4Hs different from the hypoxia-inducible factor P4Hs. Key structural differences between these two subgroups are described. These studies provide first insight into the structure-function relationships of the collagen P4Hs, which unlike the hypoxia-inducible factor P4Hs use proline-rich peptides as their substrates.

Received for publication, August 8, 2007 , and in revised form, October 16, 2007.

The atomic coordinates and structure factors (code 2V4A, 2JIJ, and 2JIG) 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 a EU-BIOXHIT grant (to R. K. W.), by the Academy of Finland Grants 200966 (to R. K. W.), 115124 (to M. K. K.), and 203574, 200965, and 211128 (to J. M.), and by the Sigrid Juelius Foundation and FibroGen Inc. (to J. M.). 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: P. O. Box 3000, University of Oulu, FIN-90014 Oulu, Finland. Tel.: 358-8-5531199; Fax: 358-8-5531141; E-mail: rik.wierenga{at}oulu.fi.

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