后生动物氧感应的进化涉及 VHL 对 HIF1α 和 HIF2α 的亲和力的保守差异。
Evolution of metazoan oxygen-sensing involved a conserved divergence of VHL affinity for HIF1α and HIF2α.
机构信息
Department of Laboratory Medicine & Pathobiology, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
Department of Biochemistry, University of Toronto, 661 University Avenue, Toronto, ON, M5G 1M1, Canada.
出版信息
Nat Commun. 2019 Jul 23;10(1):3293. doi: 10.1038/s41467-019-11149-1.
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.
祖先缺氧诱导因子 (HIF)α 的复制与脊椎动物物种的进化同时发生。HIF1α 和 HIF2α 是最著名的两种因子，可调节缺氧后细胞的转录谱。然而，自然选择过程如何作用于这两个基因的编码区，以优化进化过程中细胞对缺氧的反应仍不清楚。HIFα 的关键负调节因子是 von Hippel-Lindau (VHL) 肿瘤抑制蛋白。在这里，我们表明进化相关的取代可以调节 HIF1α Met561 和 VHL Phe91 之间的二次接触。值得注意的是，由于在脊椎动物谱系中观察到保守的 Met 到 Thr 取代，HIF1α 比 HIF2α 更紧密地结合 VHL。同样，VHL Phe91 被 Invertebrate 物种中所见的 Tyr 取代，降低了 VHL 对 HIF1α 和 HIF2α 的亲和力。我们提出，脊椎动物的进化涉及到更复杂的缺氧反应，VHL 对 HIF1α 和 HIF2α 的亲和力发生了精细的分歧。
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