Evolution of metazoan oxygen-sensing involved a conserved divergence of VHL affinity for HIF1α and HIF2α

Duplication of ancestral hypoxia-inducible factor (HIF)alpha coincided with the evolution of vertebrate species. Paralogs HIF1 alpha and HIF2 alpha are the most well-known factors for modulating the cellular transcriptional profile following hypoxia. However, how the processes of natural selection acted upon the coding region of these two genes to optimize the cellular response to hypoxia during evolution remains unclear. A key negative regulator of HIF alpha is von Hippel-Lindau (VHL) tumour suppressor protein. Here we show that evolutionarily-relevant substitutions can modulate a secondary contact between HIF1 alpha Met561 and VHL Phe91. Notably, HIF1 alpha binds more tightly than HIF2 alpha to VHL due to a conserved Met to Thr substitution observed in the vertebrate lineage. Similarly, substitution of VHL Phe91 with Tyr, as seen in invertebrate species, decreases VHL affinity for both HIF1 alpha and HIF2 alpha. We propose that vertebrate evolution involved a more complex hypoxia response with fine-tuned divergence of VHL affinity for HIF1 alpha and HIF2 alpha.