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首页> 外文期刊>Biochemistry >Total alanine-scanning mutagenesis of insulin-like growth factor I (IGF-I) identifies differential binding epitopes for IGFBP-1 and IGFBP-3.
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Total alanine-scanning mutagenesis of insulin-like growth factor I (IGF-I) identifies differential binding epitopes for IGFBP-1 and IGFBP-3.

机译：胰岛素样生长因子I（IGF-1）的总丙氨酸扫描诱变确定了IGFBP-1和IGFBP-3的差异结合表位。

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摘要

The bioavailability of insulin-like growth factor I (IGF-I) in the serum and tissues is controlled by members of the IGF binding protein family (IGFBP). These proteins form high-affinity complexes with IGF-I and thereby either inhibit or potentiate its mitogenic and metabolic effects. Thus, understanding the IGF-IGFBP interaction at the molecular level is crucial for attempts to modulate IGF-I activity in vivo. We have systematically investigated the binding contribution of each IGF-I amino acid side chain toward IGFBP-1 and IGFBP-3, combining alanine-scanning mutagenesis and monovalent phage display. Surprisingly, most IGF-I residues could be substituted by alanines, resulting in less than 5-fold affinity losses for IGFBP-3. In contrast, binding of IGFBP-1 was more sensitive to alanine substitutions in IGF-I. The glutamate and phenylalanine at positions 3 and 49 were identified as major specificity determinants for IGFBP-1: the corresponding alanine mutations, E3A and F49A, selectively decreased IGFBP-1 binding by 34- and 100-fold, whereas IGFBP-3 affinity was not affected or reduced maximally 4-fold. No side chain specificity determinant was found for IGFBP-3. Instead, our results suggest that the N-terminal backbone region of IGF-I is important for binding to IGFBP-3. The fact that the functional binding epitopes on IGF-I are overlapping but distinct for both binding proteins may be exploited to design binding protein-specific IGF variants.
机译：胰岛素样生长因子I（IGF-1）在血清和组织中的生物利用度由IGF结合蛋白家族（IGFBP）的成员控制。这些蛋白质与IGF-1形成高亲和力复合物，从而抑制或增强其促有丝分裂和代谢作用。因此，在分子水平上理解IGF-IGFBP相互作用对于调节体内IGF-1活性的尝试至关重要。我们已经结合丙氨酸扫描诱变和单价噬菌体展示，系统地研究了每个IGF-1氨基酸侧链对IGFBP-1和IGFBP-3的结合贡献。出乎意料的是，大多数IGF-I残基可以被丙氨酸取代，导致对IGFBP-3的亲和力损失少于5倍。相反，IGFBP-1的结合对IGF-1中的丙氨酸取代更敏感。在3和49位的谷氨酸和苯丙氨酸被确定为IGFBP-1的主要特异性决定因素：相应的丙氨酸突变E3A和F49A选择性地使IGFBP-1结合降低了34倍和100倍，而对IGFBP-3的亲和力却没有影响或减少最多4倍。没有发现IGFBP-3的侧链特异性决定因素。相反，我们的结果表明，IGF-1的N末端骨架区域对于结合IGFBP-3很重要。可以利用IGF-1上的功能性结合表位重叠但对于两种结合蛋白不同的事实来设计结合蛋白特异性IGF变体。

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