Structural basis for the recognition of hydroxyproline in αIF-1α by pVHL
Structural basis for the recognition of hydroxyproline in αIF-1α by pVHL
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DOI：
10.1038/nature00767
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发表时间：
2002-06-27
期刊：
影响因子：
64.8
通讯作者：
Jones, EY
中科院分区：
文献类型：
--
作者：
Hon, WC;Wilson, MI;Jones, EY
缺氧诱导因子-1(HIF-1)是一种转录复合体，控制细胞和系统对氧气供应的稳态反应(1)。HIF-1α是HIF-1的氧调节亚基，是一种α-β异二聚体复合体(1)。HIF-1α在低氧条件下是稳定的，但在氧气存在时，它的目标是泛素化复合体pVHL的蛋白酶体降解，pVHL是von Hippel-Lindau(VHL)肿瘤抑制基因的蛋白质，也是E3泛素连接酶复合体(2，3)的一个组成部分。PVHL对HIF-1α的捕获是通过对HIF-1α(4-7)两个功能独立区域中特定Pro残基的羟化来调节的。与VCB(pVHL，细长蛋白C和B)结合的羟化HIF-1α多肽的晶体结构和溶液结合分析表明，pVHL中有一个单一的、保守的羟脯氨酸结合口袋。优化的氢键与埋藏的羟脯氨酸基团结合，可精确区分羟基化和未修饰的羟丙基残基。这一机制为开发治疗药物以调节细胞对低氧的反应提供了新的焦点。
Hypoxia-inducible factor-1 (HIF-1) is a transcriptional complex that controls cellular and systemic homeostatic responses to oxygen availability(1). HIF-1alpha is the oxygen-regulated subunit of HIF-1, an alphabeta heterodimeric complex(1). HIF-1alpha is stable in hypoxia, but in the presence of oxygen it is targeted for proteasomal degradation by the ubiquitination complex pVHL, the protein of the von Hippel-Lindau (VHL) tumour suppressor gene and a component of an E3 ubiquitin ligase complex(2,3). Capture of HIF-1alpha by pVHL is regulated by hydroxylation of specific prolyl residues in two functionally independent regions of HIF-1alpha(4-7). The crystal structure of a hydroxylated HIF-1alpha peptide bound to VCB (pVHL, elongins C and B) and solution binding assays reveal a single, conserved hydroxyproline-binding pocket in pVHL. Optimized hydrogen bonding to the buried hydroxyprolyl group confers precise discrimination between hydroxylated and unmodified prolyl residues. This mechanism provides a new focus for development of therapeutic agents to modulate cellular responses to hypoxia.