A novel binding site for the human insulin-like growth factor-II (IGF-II)/mannose 6-phosphate receptor on IGF-II
A novel binding site for the human insulin-like growth factor-II (IGF-II)/mannose 6-phosphate receptor on IGF-II
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DOI：
10.1074/jbc.m700531200
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发表时间：
2007-06-29
影响因子：
4.8
通讯作者：
Forbes, Briony E.
中科院分区：
文献类型：
--
作者：
Delaine, Carlie;Alvino, Clair L.;Forbes, Briony E.
哺乳动物胰岛素样生长因子（IGF）-II/阳离子非依赖性甘露糖6-磷酸受体（IGF 2 R）以高亲和力结合IGF-II。通过将IGF-II靶向溶酶体降解，它在维持循环和靶组织中正确的IGF-II水平方面发挥作用。IGF 2 R功能的丧失与肿瘤进展相关;因此，IGF 2 R通常被称为肿瘤抑制因子。IGF 2 R和IGF-II之间的相互作用涉及受体的15个胞外结构域中的结构域11和13。最近，在IGF 2 R的结构域11上鉴定了疏水结合区。相比之下，对IGF-II中参与IGF 2 R结合的残基以及IGF 2 R对IGF-II的特异性超过结构相关的IGF-I的决定因素知之甚少。使用一系列新的IGF-II类似物和表面等离子体共振分析，这项研究揭示了一种新的结合表面的IGF-II的关键IGF 2 R的结合。疏水残基Phe 19和Leu 53对于IGF 2 R结合至关重要，残基Thr 16和Asp 52也是如此。此外，Thr 16被鉴定为在确定为什么IGF-II而不是IGF-I以高亲和力结合IGF 2 R中起主要作用。
The mammalian insulin-like growth factor (IGF)-II/cation-independent mannose 6-phosphate receptor (IGF2R) binds IGF-II with high affinity. By targeting IGF-II to lysosomal degradation, it plays a role in the maintenance of correct IGF-II levels in the circulation and in target tissues. Loss of IGF2R function is associated with tumor progression; therefore, the IGF2R is often referred to as a tumor suppressor. The interaction between IGF2R and IGF-II involves domains 11 and 13 of the 15 extracellular domains of the receptor. Recently, a hydrophobic binding region was identified on domain 11 of the IGF2R. In contrast, relatively little is known about the residues of IGF-II that are involved in IGF2R binding and the determinants of IGF2R specificity for IGF-II over the structurally related IGF-I. Using a series of novel IGF-II analogues and surface plasmon resonance assays, this study revealed a novel binding surface on IGF-II critical for IGF2R binding. The hydrophobic residues Phe19 and Leu53 are critical for IGF2R binding, as are residues Thr16 and Asp52. Furthermore, Thr16 was identified as playing a major role in determining why IGF-II, but not IGF-I, binds with high affinity to the IGF2R.