Computational analysis reveals that polycythemia-causing PHD2 mutations primarily affect a novel binding interface rather than the catalytic site, potentially disrupting interaction with the LIMD1 tumor suppressor.
Does not yet alter polycythemia management; leaves open PHD2-LIMD1 interface as a therapeutic target.
Idiopathic erythrocytosis is a rare disease characterized by an increase in red blood cell mass due to mutations in proteins of the oxygen-sensing pathway, such as prolyl hydroxylase 2 (PHD2). Here, we present a bioinformatics investigation of the pathological effect of twelve PHD2 mutations related to polycythemia insurgence. We show that few mutations impair the PHD2 catalytic site, while most localize to non-enzymatic regions. We also found that most mutations do not overlap the substrate recognition site, suggesting a novel PHD2 binding interface. After a structural analysis of both binding partners, we suggest that this novel interface is responsible for PHD2 interaction with the LIMD1 tumor suppressor.
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Minervini et al. (2016) studied this question.
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