Cobalt inhibits the interaction between hypoxia-inducible factor-α and von Hippel-Lindau protein by direct binding to hypoxia-inducible factor-α
Cobalt inhibits the interaction between hypoxia-inducible factor-α and von Hippel-Lindau protein by direct binding to hypoxia-inducible factor-α
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DOI：
10.1074/jbc.m300463200
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发表时间：
2003-05-02
影响因子：
4.8
通讯作者：
Millhorn, DE
中科院分区：
文献类型：
--
作者：
Yuan, Y;Hilliard, G;Millhorn, DE
缺氧诱导因子（HIF）能激活含有缺氧反应元件的基因表达。在常氧条件下，HIF转录因子的α亚基通过蛋白酶体途径降解，但在缺氧条件下则保持稳定。希佩尔 - 林道蛋白（pVHL）介导HIF -α（包括HIF - 1α和HIF - 2α）的泛素化和快速降解。HIF -α的氧依赖降解（ODD）结构域中的一个脯氨酸残基发生翻译后羟基化是HIF与VHL相互作用所必需的。先前已经确定钴模拟缺氧并导致HIF - 1α和HIF - 2α的积累。然而，对于这种情况发生的机制知之甚少。在早期的一项研究中，我们证明了钴直接与HIF - 2α的ODD结构域结合。在此我们提供了第一个证据，即即使当HIF -α被羟基化时，钴也会抑制pVHL与HIF -α的结合。在HIF - 2α的ODD结构域内删除pVHL结合所必需的17个氨基酸，可阻止钴的结合，并在常氧条件下使HIF - 2α保持稳定。这些发现表明，钴至少在一定程度上通过占据HIF -α的VHL结合结构域来模拟缺氧，从而阻止HIF -α的降解。
The hypoxia-inducible factor (HIF) activates the expression of genes that contain a hypoxia response element. 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-alpha (including HIF-1alpha and HIF-2alpha). Post-translational hydroxylation of a proline residue in the oxygen-dependent degradation (ODD) domain of HIF-alpha is required for the interaction between HIF and VHL. It has previously been established that cobalt mimics hypoxia and causes accumulation of HIF-1alpha and HIF-2alpha. However, little is known about the mechanism by which this occurs. In an earlier study, we demonstrated that cobalt binds directly to the ODD domain of HIF-2alpha. Here we provide the first evidence that cobalt inhibits pVHL binding to HIF-alpha even when HIF-alpha is hydroxylated. Deletion of 17 amino acids within the ODD domain of HIF-2alpha that are required for pVHL binding prevented the binding of cobalt and stabilized HIF-2alpha during normoxia. These findings show that cobalt mimics hypoxia, at least in part, by occupying the VHL-binding domain of HIF-alpha and thereby preventing the degradation of HIF-alpha.