title: In silico investigation of PHD-3 specific HIF1-α proline 567 hydroxylation: a new player in the VHL/HIF-1α interaction pathway?
abstract: Hypoxia inducible factor 1α (HIF-1α) regulates oxygen homeostasis in the cell through a sensing mechanism involving its hydroxylation and binding to the von Hippel-Lindau (VHL) tumor suppressor. This mechanism is mediated through hydroxylation of HIF-1α proline 564, although in vitro tests have previously shown an alternative hydroxylation at proline 567 by PHD-3. Here, molecular dynamics simulations were used to investigate the structural effect of this alternative hydroxylation. A specific hydrogen bond network rearrangement and improved electrostatic energy for hydroxylated P567 are compatible with an increase in HIF-1α binding affinity. Sequence analysis also confirms P567 to be vastly conserved during evolution, indicating a possible role for this alternative, PHD-3 driven, post translational modification in pVHL-HIF-1α complex formation.
authors.affiliation: Dept. of Biology, University of Padova, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Minervini
authors.forename: Alessandro
authors.initials: A
authors.lastname: Masiero
authors.forename: Stefano
authors.initials: S
authors.lastname: Moro
authors.forename: Silvio C E
authors.initials: SC
authors.lastname: Tosatto
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D017124:Conserved Sequence; D049308:Dioxygenases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D006900:Hydroxylation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D055672:Static Electricity; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D049308:Dioxygenases; C488894:EGLN3 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human
keywords: Cancer; Hypoxia inducible factor 1; Molecular dynamic; Sequence analysis; Structural bioinformatic; von Hippel–Lindau