Mechanism of transmembrane signaling: Insulin binding and the insulin receptor
Mechanism of transmembrane signaling: Insulin binding and the insulin receptor
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DOI：
10.1021/bi0015921
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发表时间：
2000-10-10
期刊：
影响因子：
2.9
通讯作者：
Yip, CC
中科院分区：
文献类型：
--
作者：
Ottensmeyer, FP;Beniac, DR;Yip, CC
通过受体酪氨酸激酶的跨膜信号传导通常需要受体单体的寡聚化，伴随受体胞外结构域的配体诱导的二聚体或更高的多聚体的形成。预期这样的形成将细胞内激酶结构域以正确的距离和方向并置以进行转磷酸化。对于胰岛素受体家族中组成型二聚体的受体，或那些在没有配体的情况下形成非共价二聚体的受体，其机制必须更加复杂。对于这些，构象必须通过配体从阻止激活的构象改变为允许激酶磷酸化的构象。自从20多年前发现胰岛素受体以来，胰岛素配体如何实现这一作用一直是一个谜，主要是因为膜蛋白一般难以通过晶体学确定结构。然而，已经获得了胰岛素受体和类似蛋白质的各个独立亚结构域的高分辨率结构证据。最近解决的四级结构的完整的二聚体胰岛素受体在胰岛素的存在下，现在已经作为结构的信封，这些个别的域被安装到。结合结构提供了答案的细节胰岛素/受体相互作用的结合位点和跨膜信号的这种共价二聚体的机制。该结构解释了有关受体行为的许多观察结果，从胰岛素及其变体、受体的点突变体和缺失突变体的或多或少的结合，到抗体结合模式，以及对基础和胰岛素刺激的自磷酸化的影响。温和的还原条件。
Transmembrane signaling via receptor tyrosine kinases generally requires oligomerization of receptor monomers, with the formation of ligand-induced dimers or higher multimers of the extracellular domains of the receptors. Such formations are expected to juxtapose the intracellular kinase domains at the correct distances and orientations for transphosphorylation. For receptors of the insulin receptor family that are constitutively dimeric, or those that form noncovalent dimers without ligands, the mechanism must be more complex. For these, the conformation must be changed by the ligand from one that prevents activation to one that is permissive for kinase phosphorylation. How the insulin ligand accomplishes this action has remained a puzzle since the discovery of the insulin receptor over 2 decades ago, primarily because membrane proteins in general have been refractory to structure determination by crystallography. However, high-resolution structural evidence on individual separate subdomains of the insulin receptor and of analogous proteins has been obtained. The recently solved quaternary structure of the complete dimeric insulin receptor in the presence of insulin has now served as the structural envelope into which such individual domains were fitted. The combined structure has provided answers on the details of insulin/receptor interactions in the binding site and on the mechanism of transmembrane signaling of this covalent dimer. The structure explains many observations on the behavior of the receptor, from greater or lesser binding of insulin and its variants, point and deletion mutants of the receptor, to antibody-binding patterns, and to the effects on basal and insulin-stimulated autophosphorylation under mild reducing conditions.