An Erythrocytosis-Associated Mutation in the Zinc Finger of PHD2 Provides Insights into Its Binding of p23
Received 10 September 2019
Accepted for publication 16 October 2019
Published 13 December 2019 Volume 2019:7 Pages 81—86
Checked for plagiarism Yes
Review by Single-blind
Peer reviewer comments 3
Editor who approved publication: Prof. Dr. Dörthe Katschinski
Daisheng Song,1 Wei Guan,1–3 Lea M Coon,4 Aref Al-Kali,5 Jennifer L Oliveira,4 Frank S Lee1
1Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; 2Department of Ultrasound, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People’s Republic of China; 3Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, People’s Republic of China; 4Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA; 5Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
Correspondence: Frank S Lee
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, 605 Stellar Chance Bldg, 422 Curie Blvd, Philadelphia, PA 19104, USA
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Background: 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.
Results: 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.
Conclusion: 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.
Keywords: EGLN1, erythropoietin, hypoxia inducible factor, prolyl hydroxylase domain protein 2, polycythemia
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