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In silico investigation of PHD‐3 specific HIF1‐α proline 567 hydroxylation: A new player in the VHL/HIF‐1α interaction pathway?
Author(s) -
Minervini Giovanni,
Masiero Alessandro,
Moro Stefano,
Tosatto Silvio C.E.
Publication year - 2013
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2013.07.019
Subject(s) - hydroxylation , proline , chemistry , in silico , hypoxia inducible factor 1 , hypoxia inducible factors , biochemistry , stereochemistry , microbiology and biotechnology , biophysics , enzyme , biology , amino acid , transcription factor , gene
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.