Prolyl hydroxylase domain protein 2 (PHD2) binds a Pro-Xaa-Leu-Glu motif, linking it to the heat shock protein 90 pathway

J Biol Chem. 2013 Apr 5;288(14):9662-74. doi: 10.1074/jbc.M112.440552. Epub 2013 Feb 14.

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 this 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 Xaa = any amino 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Cell Line, Tumor
  • DNA-Binding Proteins / metabolism*
  • HEK293 Cells
  • HSP90 Heat-Shock Proteins / metabolism*
  • HeLa Cells
  • Humans
  • Hypoxia
  • Hypoxia-Inducible Factor 1, alpha Subunit / chemistry*
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Mass Spectrometry / methods
  • Models, Biological
  • Molecular Sequence Data
  • Plasmids / metabolism
  • Procollagen-Proline Dioxygenase / chemistry
  • Procollagen-Proline Dioxygenase / metabolism
  • Procollagen-Proline Dioxygenase / physiology*
  • Protein Structure, Tertiary
  • RNA, Small Interfering / metabolism

Substances

  • DNA-Binding Proteins
  • HSP90 Heat-Shock Proteins
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Small Interfering
  • protein p23
  • EGLN1 protein, human
  • Procollagen-Proline Dioxygenase
  • Hypoxia-Inducible Factor-Proline Dioxygenases