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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The design and characterization of two proteins with 88% sequence identity but different structure and function
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The design and characterization of two proteins with 88% sequence identity but different structure and function

机译：具有88％序列同一性但结构和功能不同的两种蛋白质的设计和表征

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摘要

To identify a simplified code for conformational switching, we have redesigned two natural proteins to have 88% sequence identity but different tertiary structures: a 3-α helix fold and an α/β fold. We describe the design of these homologous heteromorphic proteins, their structural properties as determined by NMR, their conformational stabilities, and their affinities for their respective ligands: IgG and serum albumin. Each of these proteins is completely folded at 25℃, is monomeric, and retains the native binding activity. The complete binding epitope for both ligands is encoded within each of the proteins. The IgG-binding epitope is functional only in the α/β fold, and the albumin-binding epitope is functional only in the 3-α fold. These results demonstrate that two monomeric folds and two different functions can be encoded with only 12% of the amino acids in a protein (7 of 56). The fact that 49 aa in these proteins are compatible with both folds shows that the essential information determining a fold can be highly concentrated in a few amino acids and that a very limited subset of interactions in the protein can tip the balance from one monomer fold to another. This delicate balance helps explain why protein structure prediction is so challenging. Furthermore, because a few mutations can result in both new conformation and new function, the evolution of new folds driven by natural selection for alternative functions may be much more probable than previously recognized.
机译：为了确定构象转换的简化代码，我们重新设计了两种天然蛋白质，它们具有88％的序列同一性但三级结构不同：3-α螺旋折叠和α/β折叠。我们描述了这些同源异质蛋白的设计，通过NMR确定的结构特性，其构象稳定性以及它们对各自配体的亲和力：IgG和血清白蛋白。这些蛋白质中的每一个都在25℃下完全折叠，是单体的，并保留了天然的结合活性。两个配体的完整结合表位在每个蛋白质中编码。结合IgG的表位仅在α/β折叠中起作用，而结合白蛋白的表位仅在3-α折叠中起作用。这些结果表明，蛋白质中只有12％的氨基酸可以编码两个单体折叠和两个不同的功能（56个中的7个）。这些蛋白质中的49个氨基酸与两个折叠都相容的事实表明，决定一个折叠的基本信息可以高度集中在几个氨基酸中，并且蛋白质中相互作用的非常有限的子集可以使平衡从一个单体折叠变为另一个。这种微妙的平衡有助于解释为什么蛋白质结构预测如此具有挑战性。此外，由于一些突变会导致新的构象和新功能，因此自然选择替代功能所驱动的新折叠的进化可能比以前认识到的要多得多。

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