title: Computational analysis of prolyl hydroxylase domain-containing protein 2 (PHD2) mutations promoting polycythemia insurgence in humans.
abstract: 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.
authors.affiliation: Department of Biomedical Sciences and CRIBI Biotechnology Center, University of Padova, Viale G. Colombo 3, 35121, Padova, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Minervini
authors.affiliation: Department of Biomedical Sciences and CRIBI Biotechnology Center, University of Padova, Viale G. Colombo 3, 35121, Padova, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Quaglia
authors.affiliation: Department of Biomedical Sciences and CRIBI Biotechnology Center, University of Padova, Viale G. Colombo 3, 35121, Padova, Italy.|CNR Institute of Neuroscience, Viale G. Colombo 3, 35121, Padova, Italy.
authors.forename: Silvio C E
authors.initials: SC
authors.lastname: Tosatto
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D017124:Conserved Sequence; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation; D020125:Mutation, Missense; D011086:Polycythemia / Q000235:genetics* / Q000378:metabolism; D056510:Position-Specific Scoring Matrices; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D060066:Protein Interaction Maps; D055550:Protein Stability; D017422:Sequence Analysis, DNA
chemical_list: C490190:EGLN1 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases