An Erythrocytosis-Associated Mutation in the Zinc Finger of PHD2 Provides Insights into Its Binding of p23

• Published in: Hypoxia 2019-01, Vol.7, p.81-86
• Main Authors: Song, Daisheng, Guan, Wei, Coon, Lea M, Al-Kali, Aref, Oliveira, Jennifer L, Lee, Frank S
• Format: Article
• Language: English
• Subjects: Cancer; Experiments; Genes; Hypoxia; Laboratories; Medicine; Mutation; Original Research; Pathology; Proteins
• ISSN: 2324-1128; 2324-1128
• DOI: 10.2147/HP.S230502

Loss of function mutations in the gene are a cause of erythrocytosis. encodes for prolyl hydroxylase domain protein 2 (PHD2). PHD2 hydroxylates and downregulates hypoxia-inducible factor-2α (HIF-2α), a transcription factor that regulates erythropoiesis. While the large majority of erythrocytosis-associated mutations occur within its catalytic domain, rare mutations reside in its zinc finger. This zinc finger binds a Pro-Xaa-Leu-Glu motif in p23, an HSP90 cochaperone that facilitates hydroxylation of HIF-α, an HSP90 client. Essentially nothing is known about the specific interactions between the PHD2 zinc finger and p23. Here, we characterize an erythrocytosis-associated mutation in the zinc finger, K55N, that abolishes interaction with p23. We provide evidence that the affected residue, Lys-55, interacts with Asp-152 of p23. We also present results that indicate that PHD2 Arg-32 interacts with p23 Glu-160. These studies not only reinforce the importance of the PHD2 zinc finger in the control of erythropoiesis, but also lead to a model in which a peptide motif in p23 binds in a specific orientation to a predicted groove in the zinc finger of PHD2.