THE STRUCTURAL BASIS OF INSULIN AND INSULIN-LIKE GROWTH-FACTOR-I RECEPTOR-BINDING AND NEGATIVE COOPERATIVITY, AND ITS RELEVANCE TO MITOGENIC VERSUS METABOLIC SIGNALING
THE STRUCTURAL BASIS OF INSULIN AND INSULIN-LIKE GROWTH-FACTOR-I RECEPTOR-BINDING AND NEGATIVE COOPERATIVITY, AND ITS RELEVANCE TO MITOGENIC VERSUS METABOLIC SIGNALING
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DOI：
10.1007/bf00400837
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发表时间：
1994-09-01
期刊：
影响因子：
8.2
通讯作者：
DEMEYTS, P
中科院分区：
文献类型：
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作者：
DEMEYTS, P
胰岛素和胰岛素样生长因子-I表现出一组非经典的受体结合特性，提示这两个受体之间存在负的协同作用或位点间的相互作用：曲线Scatchard图，在未标记配体存在的情况下，结合的标记配体在高稀释时加速解离。α(2)β(2)受体二聚体只与一个高亲和力的配体分子结合。未标记胰岛素对I-125-胰岛素的剂量-效应曲线呈钟形，当胰岛素浓度超过0.1mU·mol/L时，负协同效应消失，这一现象被归因于胰岛素二聚，但非二聚类似物和胰岛素在六聚体形成面上修饰的新数据表明，胰岛素分子的六角体表面存在第二结合位点。这个位点与受体上的第二个结构域结合。提出了一种新的胰岛素和胰岛素样生长因子-I的结合模型，其中二价配体在对称受体结构中的相对位置交替桥接两个受体α亚基。在胰岛素和胰岛素样生长因子-I性质演变的背景下，讨论了该模型对负协作性、钟形生物曲线以及有丝分裂和代谢信号之间的差异的影响。
Insulin and insulin-like growth factor-I exhibit a set of non-classical receptor binding properties suggestive of negative co-operativity or site-site interactions between the two receptor halves: curvilinear Scatchard plots, acceleration of dissociation of bound labelled ligand at high dilution in the presence of unlabelled ligand. The alpha(2) beta(2) receptor dimer binds only one ligand molecule with high affinity. The dose-response curve for the acceleration of I-125-insulin by unlabelled insulin is bell-shaped, with a disappearance of the negative co-operativity at insulin concentrations over 0.1 mu mol/l. This phenomenon had been attributed to insulin dimerization, but new data with non-dimerizing analogues and insulins modified at the hexamer-forming surface indicate the presence of a second binding site on the insulin molecule's hexamer face. This site binds to a second domain on the receptor. A new binding model for insulin and insulin-like growth factor-I is proposed where the bivalent ligand bridges the two receptor alpha subunits alternatively at opposite sites in a symmetrical receptor structure. The implications of the model for negative co-operativity, bell-shaped biological curves, and the divergence between mitogenic and metabolic signalling are discussed in the context of the evolution of the properties of insulin and insulinlike growth factor-I.