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Hypoxia (Auckl). 2019 Dec 13;7:81-86. doi: 10.2147/HP.S230502. eCollection 2019.

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

Author information

1
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
2
Department of Ultrasound, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China.
3
Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, People's Republic of China.
4
Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
5
Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.

Abstract

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; polycythemia; prolyl hydroxylase domain protein 2

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