Abstract
Duplication of ancestral hypoxia-inducible factor (HIF)α coincided with the evolution of vertebrate species. Paralogs HIF1α and HIF2α 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 HIFα is von Hippel-Lindau (VHL) tumour suppressor protein. Here we show that evolutionarily-relevant substitutions can modulate a secondary contact between HIF1α Met561 and VHL Phe91. Notably, HIF1α binds more tightly than HIF2α 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 HIF1α and HIF2α. We propose that vertebrate evolution involved a more complex hypoxia response with fine-tuned divergence of VHL affinity for HIF1α and HIF2α.
Highlights
Duplication of ancestral hypoxia-inducible factor (HIF)α coincided with the evolution of vertebrate species
As it has been suggested that HIF2α is less efficiently degraded when compared to HIF1α, we hypothesized that HIF1α may interact more strongly with von HippelLindau (VHL)
We observed that hydroxylated HIF1α peptide (556–573) pulls down more in vitro transcribed and translated (IVTT) HA-VHL than HIF2α peptide (523–541; Fig. 1a)
Summary
Duplication of ancestral hypoxia-inducible factor (HIF)α coincided with the evolution of vertebrate species. Metazoan oxygen-sensing requires hypoxia-inducible factor (HIF)α proteins[1]. HIFα escapes both hydroxylation via PHDs and recognition via VHL allowing its dimerization with the constitutively expressed HIFβ protein. This dimerization results in the formation of a functional transcription factor that upregulates expression of angiogenic factors, glycolytic enzymes, and signallers of erythropoiesis, among other genes. PHD cloned from T. adhaerens can function to regulate HIFα when expressed in human cells, suggesting remarkable conservation of this pathway during metazoan evolution[7]. There is high structural conservation between HIF1α and HIF2α basic helix loop helix (bHLH) and PER-ARNT-SIM (PAS) domains, which are responsible for DNA binding and dimerization with HIFβ, respectively[13]
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