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

Song, Daisheng; Li, Linsheng; Heaton-Johnson, Katherine J.; Arsenault, Patrick R.; Master, Stephen R.; Lee, Frank S.

doi:10.1074/jbc.m112.440552

Cited by 54 publications

(86 citation statements)

References 54 publications

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“…Plasmids-pcDNA3-HA-PHD2 (1-131) was constructed by subcloning the 0.4-kb BamHI/NotI (partial digest) fragment encoding residues 1-131 of pcDNA3-HA-PHD2 (19) into the BamHI/NotI site of pcDNA3-HA. pcDNA3-HA-PHD2 (1-173) was constructed by digesting pcDNA3-HA-PHD2 with BlpI/XhoI, blunting the ends with the Klenow fragment of Escherichia coli DNA polymerase I, and then religating.…”

Section: Methodsmentioning

confidence: 99%

“…pcDNA3-HA-PHD2 (1-173) D4E/C127S was constructed by digesting pcDNA3-HA-PHD2 (1-196) D4E/C127S with BlpI/ XhoI, blunting the ends with the Klenow fragment of E. coli DNA polymerase I, and then religating. pcDNA3-HA-PHD2 D4E/C127S was constructed by subcloning the 0.6-kb BamHI/ XhoI fragment from pcDNA3-HA-PHD2 (1-196) D4E/C127S into the BamHI/XhoI site of pcDNA3-HA-PHD2 (130 -426) (19). pcDNA5/FRT/TO-FlagPHD2 D4E/C127S was constructed by subcloning the 0.6-kb BamHI/XhoI fragment of pcDNA3-HA-PHD2 (1-196) D4E/C127S into the BamHI/ XhoI site of pcDNA5/FRT/TO-FlagPHD2 (19).…”

Section: Methodsmentioning

confidence: 99%

“…pcDNA3-HA-PHD2 D4E/C127S was constructed by subcloning the 0.6-kb BamHI/ XhoI fragment from pcDNA3-HA-PHD2 (1-196) D4E/C127S into the BamHI/XhoI site of pcDNA3-HA-PHD2 (130 -426) (19). pcDNA5/FRT/TO-FlagPHD2 D4E/C127S was constructed by subcloning the 0.6-kb BamHI/XhoI fragment of pcDNA3-HA-PHD2 (1-196) D4E/C127S into the BamHI/ XhoI site of pcDNA5/FRT/TO-FlagPHD2 (19). pcDNA3-FlagPHD2 D4E/C127S was constructed by subcloning the 0.6 kb BamHI/XhoI fragment of pcDNA3-HA-PHD2 (1-196) D4E/C127S into the BamHI/XhoI site of pcDNA3-FlagPHD2 (23).…”

Section: Methodsmentioning

confidence: 99%

“…pFastBac-HT-FKBP38 (FK506-binding protein 38) was constructed by subcloning the 1.2-kb BamHI/NotI fragment of pcDNA5/FRT/TO-3ϫFlag-FKBP38 (19) into the BamHI/ NotI site of pFastBacHTc. pFastBac-HT-FlagHIF-1␣ was prepared by subcloning the 3.2-kb BamHI/XbaI fragment of pcDNA3-FlagHIF-1␣ (25) into the BamHI/XbaI site of pFastBacHTb.…”

Section: Methodsmentioning

confidence: 99%

“…This zinc finger shows strong phylogenetic conservation (17,18) and in fact is present in the PHD2 orthologue in the simplest metazoan, Trichoplax adhaerens (17). We have recently discovered that the function of this zinc finger is to couple PHD2 to the HSP90 pathway (19). Specifically, it binds to a Pro-Xaa-Leu-Glu (PXLE) motif that is present in select HSP90 cochaperones such as p23, and this allows recruitment of PHD2 to HSP90 to facilitate prolyl hydroxylation of HIF-1␣, which itself is an HSP90 client protein (20 -22).…”

mentioning

confidence: 99%

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Defective Tibetan PHD2 Binding to p23 Links High Altitude Adaption to Altered Oxygen Sensing

Song

Arsenault

et al. 2014

Journal of Biological Chemistry

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Defective Tibetan PHD2 Binding to p23 Links High Altitude Adaption to Altered Oxygen Sensing

Song

Arsenault

et al. 2014

Journal of Biological Chemistry

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Hypoxia as an Inducer of Inflammation

Brandwein

Deutschman

2017

Inflammation - From Molecular and Cellular Mechanisms to the Clinic

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Identification of Small‐Molecule PHD2 Zinc Finger Inhibitors that Activate Hypoxia Inducible Factor

et al. 2016

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The Prolyl Hydroxylase Domain protein (PHD):Hypoxia Inducible Factor (HIF) pathway is the main pathway by which changes in oxygen concentration are transduced to changes in gene expression. In mammals, there are three PHD paralogues, and PHD2 has emerged as a particularly critical one for regulating HIF target genes such as ERYTHROPOIETIN (EPO), which controls red cell mass and hematocrit. PHD2 is distinctive among the three PHDs in that it contains an N-terminal MYND type zinc finger. We have proposed that this zinc finger binds a Pro-Xaa-Leu-Glu (PXLE) motif found in proteins of the HSP90 pathway to facilitate HIF-α hydroxylation. Targeting it may provide a means of specifically inhibiting this PHD isoform. Here, we screened a library of chemical compounds for their capacity to inhibit the zinc finger of PHD2. We identified compounds that, in vitro, can inhibit PHD2 binding to a PXLE-containing peptide and induce activation of HIF. Injection of one of these compounds into mice induces an increase in hematocrit. This study offers proof of principle that inhibition of the zinc finger of PHD2 can provide a means of selectively targeting PHD2 to activate the HIF pathway.

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

Cited by 54 publications

References 54 publications

Defective Tibetan PHD2 Binding to p23 Links High Altitude Adaption to Altered Oxygen Sensing

Defective Tibetan PHD2 Binding to p23 Links High Altitude Adaption to Altered Oxygen Sensing

Hypoxia as an Inducer of Inflammation

Identification of Small‐Molecule PHD2 Zinc Finger Inhibitors that Activate Hypoxia Inducible Factor

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