Asparaginyl hydroxylation of the notch ankyrin repeat domain by factor inhibiting hypoxia-inducible factor
Asparaginyl hydroxylation of the notch ankyrin repeat domain by factor inhibiting hypoxia-inducible factor
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DOI：
10.1074/jbc.m704102200
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发表时间：
2007-08-17
影响因子：
4.8
通讯作者：
Schofield, Christopher J.
中科院分区：
文献类型：
--
作者：
Coleman, Mathew L.;McDonough, Michael A.;Schofield, Christopher J.
低氧诱导因子(HIF)的稳定性和活性受特定的脯氨基和天冬酰胺基残基的翻译后羟基化调控。我们发现，HIF天冬酰胺羟基酶，抑制HIF(FIH)的因子，也催化内源性Notch受体的Ankyrin Repeat(ARDS)区域内高度保守的天冬酰胺残基的羟化。AR羟化降低了ARD与FIH的结合程度，但不影响通过典型的Notch途径传递的信号。ARD蛋白被发现有效地与HIF竞争FIH依赖的羟化。对羟化的Notch ARD(2.35A)和与FIH结合的Notch多肽(2.4-2.6A)的结晶学分析揭示了AR上羟基化的立体化学，并暗示ARD折叠中需要显著的构象变化才能使FIH活性部位发生羟化。我们认为ARD蛋白是FIH的天然抑制因子，这些蛋白的羟化状态提供了另一个氧依赖的界面来调节HIF信号。
The stability and activity of hypoxia- inducible factor ( HIF) are regulated by the post- translational hydroxylation of specific prolyl and asparaginyl residues. We show that the HIF asparaginyl hydroxylase, factor inhibiting HIF ( FIH), also catalyzes hydroxylation of highly conserved asparaginyl residues within ankyrin repeat ( AR) domains ( ARDs) of endogenous Notch receptors. AR hydroxylation decreases the extent of ARD binding to FIH while not affecting signaling through the canonical Notch pathway. ARDproteins were found to efficiently compete with HIF for FIH- dependent hydroxylation. Crystallographic analyses of the hydroxylated Notch ARD ( 2.35 A) and of Notch peptides bound to FIH ( 2.4 - 2.6A) reveal the stereochemistry of hydroxylationon the AR and imply that significant conformational changes are required in the ARD fold in order to enable hydroxylation at the FIH active site. We propose that ARD proteins function as natural inhibitors of FIH and that the hydroxylation status of these proteins provides another oxygen- dependent interface that modulates HIF signaling.