Cobalt Inhibits the Interaction between Hypoxia Inducible Factor-α and von Hippel-Lindau Protein by Direct Binding to Hypoxia Inducible Factor-α

This article reveal to us the fine points of the interaction between two unique proteins hypoxia-inducible factor (HIF) (which activates the expression of genes that contain a hypoxia response element ) and hypoxia response element (HRE) We are shown the importance of von Hippel-Lindau protein (pVHL) which mediates the ubiquitination and fast degradation of HIF (both HIF1 and 2). Proline hydroxylation (post translationally) in the oxygen dependent degradation (ODD) domain of HIF is necessary for the correct interaction between HIF and VHL. The mechanism by which cobalt mimics hypoxia, causing accumulation of HIF-1 and HIF-2 is still not well understood. The authors then show initial evidence that cobalt inhibits pVHL binding to HIF, when HIF, is hydroxylated. Removing 17 amino acids within the ODD domain of HIF-2 ( normally required for pVHL binding) inhibited cobalt binding and stabilized HIF-2, during normoxia. The authors conclude that cobalt mimics hypoxia by accessing the VHL-binding domain of HIF,and in so doing prevents HIF degradation.