Defective Tibetan PHD2 Binding to p23 Links High Altitude Adaption to Altered Oxygen Sensing
Defective Tibetan PHD2 Binding to p23 Links High Altitude Adaption to Altered Oxygen Sensing
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DOI：
10.1074/jbc.m113.541227
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发表时间：
2014-05-23
影响因子：
4.8
通讯作者：
Lee, Frank S.
中科院分区：
文献类型：
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作者：
Song, Daisheng;Li, Lin-Sheng;Lee, Frank S.
藏族人口已经适应了高海拔的慢性缺氧。西藏人携带脯氨酰羟化酶结构域蛋白2（PHD 2/EGLN 1）基因的遗传特征，该基因编码缺氧诱导因子（HIF）途径的中央氧传感器。最近的研究集中在两个非同义的编码区替换，D4 E和C127 S，这两个都是显着丰富的藏族人群。这些氨基酸位于PHD 2的一个区域，该区域含有锌指，我们先前发现锌指与HSP 90辅伴侣蛋白p23中的Pro-Xaa-Leu-Glu（PXLE）基序结合，从而将PHD 2募集到HSP 90途径以促进HIF-α羟基化。我们在此报告，西藏PHD 2单倍型（D4 E/C127 S）显着减少PHD 2与p23的相互作用，导致受损的PHD 2下调HIF通路。与p23的缺陷性结合取决于D4 E和C127 S置换。我们还确定了在热休克蛋白90本身的PXLE基序，可以介导结合PHD 2，但发现这种相互作用是保持与D4 E/C127 S PHD 2单倍型。我们认为西藏PHD 2变异体是一个功能缺失（亚型）等位基因，导致增强的HIF激活，以促进适应高海拔。
The Tibetan population has adapted to the chronic hypoxia of high altitude. Tibetans bear a genetic signature in the prolyl hydroxylase domain protein 2 (PHD2/EGLN1) gene, which encodes for the central oxygen sensor of the hypoxia-inducible factor (HIF) pathway. Recent studies have focused attention on two nonsynonymous coding region substitutions, D4E and C127S, both of which are markedly enriched in the Tibetan population. These amino acids reside in a region of PHD2 that harbors a zinc finger, which we have previously discovered binds to a Pro-Xaa-Leu-Glu (PXLE) motif in the HSP90 cochaperone p23, thereby recruiting PHD2 to the HSP90 pathway to facilitate HIF-alpha hydroxylation. We herein report that the Tibetan PHD2 haplotype (D4E/C127S) strikingly diminishes the interaction of PHD2 with p23, resulting in impaired PHD2 down-regulation of the HIF pathway. The defective binding to p23 depends on both the D4E and C127S substitutions. We also identify a PXLE motif in HSP90 itself that can mediate binding to PHD2 but find that this interaction is maintained with the D4E/C127S PHD2 haplotype. We propose that the Tibetan PHD2 variant is a loss of function (hypomorphic) allele, leading to augmented HIF activation to facilitate adaptation to high altitude.