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

Authors Song D, Guan W, Coon LM, Al-Kali A, Oliveira JL, Lee FS

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
Tel +1215 898 4701
Fax +1215 573 2272

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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