| Title | A novel erythrocytosis-associated PHD2 mutation suggests the location of a HIF binding groove. | | Author(s) | Percy MJ, Furlow PW, Beer PA, Lappin TR, McMullin MF, Lee FS | | Institution | Department of Haematology, Belfast City Hospital, Belfast, Northern Ireland. | | Source | Blood 2007 Jun 19. | | Abstract | The molecular basis of the erythrocytosis group of red cell disorders is incompletely defined. Some cases are due to dysregulation of Epo synthesis. The Hypoxia Inducible transcription Factor (HIF) tightly regulates Epo synthesis. HIF in turn is regulated through its alpha-subunit, which under normoxic conditions is hydroxylated on specific prolines and targeted for degradation by the von Hippel Lindau (VHL) protein. Several mutations in VHL have been reported in erythrocytosis, but only one mutation in the HIF prolyl hydroxylase Prolyl Hydroxylase Domain protein 2 (PHD2) has been described. Here we report a novel PHD2 mutation, Arg371His, which causes decreased HIF binding, HIF hydroxylase, and HIF inhibitory activities. In the tertiary structure of PHD2, Arg-371 lies close to the previously described Pro317Arg mutation site. These findings substantiate PHD2 as a critical enzyme controlling HIF and therefore Epo in humans, and furthermore suggest the location of an active site groove in PHD2 that binds HIF. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 17579185 |
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