Studies on the substrate selectivity of the hypoxia-inducible factor prolyl hydroxylase 2 catalytic domain
In animals, the response to chronic hypoxia is mediated by upregulation of the α,β-heterodimeric hypoxia inducible factors (HIFs). Levels of HIFα isoforms, but not HIFβ, are regulated by their post-translational modification as catalysed by prolyl hydroxylase domain enzymes (PHDs). Different roles f...
| Hauptverfasser: | , , , , , , |
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| Format: | Journal article |
| Sprache: | English |
| Veröffentlicht: |
Wiley
2018
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| Zusammenfassung: | In animals, the response to chronic hypoxia is mediated by upregulation of the α,β-heterodimeric hypoxia inducible factors (HIFs). Levels of HIFα isoforms, but not HIFβ, are regulated by their post-translational modification as catalysed by prolyl hydroxylase domain enzymes (PHDs). Different roles for human HIF-1/2α isoforms and their two oxygen dependent degradation domains (ODDs) are proposed. We report kinetic and NMR analyses on the ODD selectivity of the catalytic domain of wildtype PHD2 (which is conserved in nearly all animals) and clinically observed variants. Studies using Ala-scanning and 'hybrid' ODD peptides imply the relatively rigid conformation of the (hydroxylated) proline plays an important role in ODD binding. They also reveal differential roles in binding for the residues on the N- and C-terminal sides of the substrate proline. The overall results inform on how the PHDs achieve selectivity for HIFα ODDs and may be of use in identifying substrate selective PHD inhibitors. |
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