Cobalt Inhibits the Interaction between Hypoxia Inducible Factor-α and von Hippel-Lindau Protein by Direct Binding to Hypoxia Inducible Factor-α
Yong Yuan, George Hilliard, Tsuneo Ferguson, David E. Millhorn
05/22/2014
The hypoxia-inducible factor (HIF) activates the expression of genes that contain a hypoxia response element (HRE). The alpha subunits of the HIF transcription factors are degraded by proteasomal pathways during normoxia, but are stabilized under hypoxic conditions. The von Hippel-Lindau protein (pVHL) mediates the ubiquitination and rapid degradation of HIF- α including HIF-1 oxygen dependent degradation (ODD) domain of HIF- HIF and VHL. It has previously been established that cobalt mimics hypoxia and causes accumulation of HIF-1 this occurs. In an earlier study, we demonstrated that cobalt binds directly to the ODD domain of HIF-2 when HIF- are required for pVHL binding prevented the binding of cobalt and stabilized HIF-2 normoxia. These findings show that cobalt mimics hypoxia, at least in part, by occupying VHL-binding domain of HIF- α and HIF-2α). Post-translational hydroxylation of a proline residue in theα is required for the interaction betweenα and HIF-2α. However, little is known about the mechanism by whichα. Here we provide the first evidence that cobalt inhibits pVHL binding to HIF-α evenα is hydroxylated. Deletion of 17 amino acids within the ODD domain of HIF-2α thatα duringα and thereby preventing the degradation of HIF-α.