Prolyl Hydroxylase Domain Protein 2 (PHD2) Binds a Pro-Xaa-Leu-Glu Motif, Linking it to the Heat Shock Protein 90 Pathway.

University of Pennsylvania, United States.
Journal of Biological Chemistry (Impact Factor: 4.6). 02/2013; 288(14). DOI: 10.1074/jbc.M112.440552
Source: PubMed

ABSTRACT Prolyl Hydroxylase Domain protein 2 (PHD2, also known as Egg Laying Defective Nine homolog 1) is a key oxygen-sensing protein in metazoans. In an oxygen-dependent manner, PHD2 site-specifically prolyl hydroxylates the master transcription factor of the hypoxic response, Hypoxia Inducible Factor-α (HIF-α), thereby targeting HIF-α for degradation. In the present report, we show that the Heat Shock Protein 90 (HSP90) co-chaperones p23 and FKBP38 interact via a conserved Pro-Xaa-Leu-Glu motif (where Pro = Proline, Xaa = any amino acid, Leu = Leucine, Glu = Glutamic acid) in these proteins with the N-terminal Myeloid Nervy and DEAF-1 (MYND)-type zinc finger of PHD2. Knockdown of p23 augments hypoxia-induced HIF-1α protein levels and HIF target genes. We propose that p23 recruits PHD2 to the HSP90 machinery to facilitate HIF-1α hydroxylation. These findings identify a link between two ancient pathways--the PHD:HIF and the HSP90 pathways--and suggest that this link was established concurrent with the emergence of the PHD:HIF pathway in evolution.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Humans have adapted to the chronic hypoxia of high altitude in several locations, and recent genome-wide studies have indicated a genetic basis. In some populations, genetic signatures have been identified in the hypoxia-inducible factor (HIF) pathway, which orchestrates the transcriptional response to hypoxia. In Tibetans, they have been found in the HIF2A (EPAS1) gene, which encodes for HIF-2α, and the prolyl hydroxylase domain protein 2 (PHD2, also known as EGLN1) gene, which encodes for one of its key regulators, PHD2. High-altitude adaptation may be due to multiple genes that act in concert with one another. Unraveling their mechanism of action can offer new therapeutic approaches toward treating common human diseases characterized by chronic hypoxia.
    Genes & Development 10/2014; 28(20):2189-2204. DOI:10.1101/gad.250167.114 · 12.64 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The Tibetan population has adapted to the chronic hypoxia of high altitude. Tibetans bear a genetic signature in the Prolyl Hydroxylase Domain protein 2 (PHD2/EGLN1) gene, which encodes for the central oxygen sensor of the Hypoxia Inducible Factor (HIF) pathway. Recent studies have focused attention on two nonsynonymous coding region substitutions, D4E and C127S, both of which are markedly enriched in the Tibetan population. These amino acids reside in a region of PHD2 that harbors a zinc finger, which we have previously discovered binds to a Pro-Xaa-Leu-Glu (PXLE) motif in the HSP90 cochaperone p23, thereby recruiting PHD2 to the HSP90 pathway to facilitate HIF-α hydroxylation. We now report that the Tibetan PHD2 haplotype (D4E/C127S) strikingly diminishes the interaction of PHD2 with p23, resulting in impaired PHD2 downregulation of the HIF pathway. The defective binding to p23 depends on both the D4E and C127S substitutions. We also identify a PXLE motif in HSP90 itself that can mediate binding to PHD2, but find that this interaction is maintained with the D4E/C127S PHD2 haplotype. We propose that the Tibetan PHD2 variant is a loss of function (hypomorphic) allele, leading to augmented HIF activation to facilitate adaptation to high altitude.
    Journal of Biological Chemistry 04/2014; 289(21). DOI:10.1074/jbc.M113.541227 · 4.60 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: gamma-Butyrobetaine hydroxylase (BBOX) is a 2-oxoglutarate and Fe(II) dependent oxygenase that catalyses an essential step during carnitine biosynthesis in animals. BBOX is inhibited by ejection of structural zinc by a set of selenium containing analogues. Previous structural analyses indicated that an undisrupted N-terminal zinc binding domain of BBOX is required for catalysis. Ebselen is a relatively potent BBOX inhibitor, an observation which may in part reflect its cardioprotective properties.
    Bioorganic & Medicinal Chemistry Letters 09/2014; 24(21). DOI:10.1016/j.bmcl.2014.09.035 · 2.33 Impact Factor