AI Article Synopsis
- The hydroxylation of proline residues in the HIFalpha protein is crucial for the body's response to low oxygen levels, leading to its degradation by the ubiquitin-proteasome system.
- This process enhances HIFalpha's binding to the von Hippel-Lindau protein, which tags it for destruction.
- Researchers have analyzed the structure of PHD2, a key enzyme involved in this hydroxylation, offering insights that could help create inhibitors for treating conditions like anemia and ischemic diseases.
Article Abstract
The oxygen-dependent hydroxylation of proline residues in the alpha subunit of hypoxia-inducible transcription factor (HIFalpha) is central to the hypoxic response in animals. Prolyl hydroxylation of HIFalpha increases its binding to the von Hippel-Lindau protein (pVHL), so signaling for degradation via the ubiquitin-proteasome system. The HIF prolyl hydroxylases (PHDs, prolyl hydroxylase domain enzymes) are related to the collagen prolyl hydroxylases, but form unusually stable complexes with their Fe(II) cofactor and 2-oxoglutarate cosubstrate. We report crystal structures of the catalytic domain of PHD2, the most important of the human PHDs, in complex with the C-terminal oxygen-dependent degradation domain of HIF-1alpha. Together with biochemical analyses, the results reveal that PHD catalysis involves a mobile region that isolates the hydroxylation site and stabilizes the PHD2.Fe(II).2OG complex. The results will be of use in the design of PHD inhibitors aimed at treating anemia and ischemic disease.
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| http://dx.doi.org/10.1016/j.str.2009.06.002 | DOI Listing |
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