Protein structure and the spandrels of San Marco: insulin's receptor-binding surface is buttressed by an invariant leucine essential for its stability.
Protein structure and the spandrels of San Marco: insulin's receptor-binding surface is buttressed by an invariant leucine essential for its stability.
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DOI：
10.1021/bi011839
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发表时间：
2002-01
期刊：
影响因子：
2.9
通讯作者：
M. Weiss;S. Nakagawa;W. Jia;Bin Xu;Q. Hua;Y. Chu;Run-ying Wang;P. Katsoyannis
中科院分区：
文献类型：
--
作者：
M. Weiss;S. Nakagawa;W. Jia;Bin Xu;Q. Hua;Y. Chu;Run-ying Wang;P. Katsoyannis
胰岛素提供了一个模型，诱导适合在大分子识别：激素的保守的核心，提出了一个新的受体结合表面。核心的进化不变性，在球状蛋白中是不寻常的，大概反映了结构和功能的相互交织的约束。为了探索这种不变性的结构基础，我们研究了一个关键的内部侧链（Leu（A16））的疏水取代。虽然变体表现出扰动的结构和稳定性，但保留了适度的受体结合活性。这些观察结果表明，A16侧链提供了必要的结构支撑，但与相邻的核心侧链不同，其本身不接触受体。在无脊椎动物胰岛素样蛋白中，Leu（A16）和其他假定的核心残基是不保守的，这表明脊椎动物包装方案不是胰岛素样折叠的一般要求。我们建议，保守的Leu（A16）之间的脊椎动物胰岛素和胰岛素样生长因子是一个侧面的后果诱导适合：替代包装方案是不允许的激素的隐藏的受体结合表面内缺乏周围的协变。Leu（A16）和圣马可的拱肩之间有一个类比，在圆顶拱门的交叉处有锥形的三角形空间。古尔德和列万廷的这一著名比喻强调了生物结构进化中连锁约束的作用。
Insulin provides a model of induced fit in macromolecular recognition: the hormone's conserved core is proposed to contribute to a novel receptor-binding surface. The core's evolutionary invariance, unusual among globular proteins, presumably reflects intertwined constraints of structure and function. To probe the architectural basis of such invariance, we have investigated hydrophobic substitutions of a key internal side chain (Leu(A16)). Although the variants exhibit perturbed structure and stability, moderate receptor-binding activities are retained. These observations suggest that the A16 side chain provides an essential structural buttress but unlike neighboring core side chains, does not itself contact the receptor. Among invertebrate insulin-like proteins, Leu(A16) and other putative core residues are not conserved, suggesting that the vertebrate packing scheme is not a general requirement of an insulin-like fold. We propose that conservation of Leu(A16) among vertebrate insulins and insulin-like growth factors is a side consequence of induced fit: alternative packing schemes are disallowed by lack of surrounding covariation within the hormone's hidden receptor-binding surface. An analogy is suggested between Leu(A16) and the spandrels of San Marco, tapering triangular spaces at the intersection of the dome's arches. This celebrated metaphor of Gould and Lewontin emphasizes the role of interlocking constraints in the evolution of biological structures.