Portal de Periódicos da CAPES

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

2019; Dove Medical Press; Volume: Volume 7; Linguagem: Inglês

10.2147/hp.s230502

2324-1128

Daisheng Song, Wei Guan, Lea M. Coon, Aref Al‐Kali, Jennifer L. Oliveira, Frank S. Lee,

Mitochondrial Function and Pathology

Loss of function mutations in the EGLN1 gene are a cause of erythrocytosis. EGLN1 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 EGLN1 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.