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-Prolyl-Hydroxylase 2 by a MYND-Type Zinc Finger
Department of Life Science, University of Seoul, Seoul, Korea (K.-O.C., T.L., N.L., H.P.); Life Science Division, Korea Institute of Science and Technology, Seoul, Korea (J.-H.K., E.G.Y.); and the Division of Drug Discovery, CrystalGenomics, Inc., Daejeon City, Korea (J.M.Y., J.H.K., T.G.L.)
Hypoxia-induced gene expression is initiated when the hypoxia-inducible factor-1 (HIF-1) 
subunit is stabilized in response to a lack of oxygen. An HIF-1-specific prolyl-hydroxylase (PHD) catalyzes hydroxylation of the proline-564 and/or -402 residues of HIF-1 by an oxygen molecule. The hydroxyproline then interacts with the ubiquitin E3 ligase von Hippel Lindau protein and is degraded by an ubiquitin-dependent proteasome. PHD2 is the most active of three PHD isoforms in hydroxylating HIF-1. Structural analysis showed that the N-terminal region of PHD2 contains a Myeloid translocation protein 8, Nervy, and DEAF1 (MYND)-type zinc finger domain, whereas the catalytic domain is located in its C-terminal region. We found that deletion of the MYND domain increased the activity of both recombinant PHD2 protein and in vitro-translated PHD2. The zinc chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine augmented the activity of wild-type PHD2-F but not that of PHD2 lacking the MYND domain, confirming that the zinc finger domain is inhibitory. Overexpression of PHD2 lacking the MYND domain caused a greater reduction in the stability and function of HIF-1 than did overexpression of wild-type PHD2, indicating that the MYND domain also inhibits the catalytic activity of PHD2 in vivo.
Address correspondence to: Dr. Hyunsung Park, Department of Life Science, University of Seoul, 90 Cheonnong-dong, Tongdaemun-gu, Seoul 130-743, Korea. E-mail: hspark{at}uos.ac.kr.
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