Convergent Evolution of Novel Protein Function in Shrew and Lizard Venom
Convergent Evolution of Novel Protein Function in Shrew and Lizard Venom
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DOI：
10.1016/j.cub.2009.09.022
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发表时间：
2009-12-01
期刊：
影响因子：
9.2
通讯作者：
Hoekstra, Hopi E.
中科院分区：
文献类型：
--
作者：
Aminetzach, Yael T.;Srouji, John R.;Hoekstra, Hopi E.
蛋白质是如何进化出新的功能的？为了解决这个问题，我们正在研究一种哺乳动物毒素的进化，丝氨酸蛋白酶BLTX [1]，来自北美鼩的唾液腺。在这里，我们研究负责促进BLTX毒性的分子变化。首先，我们表明，调控环周围的BLTX活性位点已经通过收购小的插入和随后的加速序列进化自适应地演变。其次，这些突变将新的化学环境引入BLTX的催化裂缝中。第三，分子动力学模拟表明，所观察到的变化创造了一种新的化学和物理拓扑结构，与酶催化作用的增加相一致。最后，我们表明，墨西哥串珠蜥蜴（GTX）[2]的有毒丝氨酸蛋白酶通过几乎相同的功能变化进化趋同。总之，这些结果表明，毒性的演变可能是可预测的，通过适应性结构修饰的祖先丝氨酸蛋白酶的类似不稳定的调节环，从而可能有助于识别其他有毒蛋白质。
How do proteins evolve novel functions? To address this question, we are studying the evolution of a mammalian toxin, the serine protease BLTX [1], from the salivary glands of the North American shrew Blarina brevicauda. Here, we examine the molecular changes responsible for promoting BLTX toxicity. First, we show that regulatory loops surrounding the BLTX active site have evolved adaptively via acquisition of small insertions and subsequent accelerated sequence evolution. Second, these mutations introduce a novel chemical environment into the catalytic cleft of BLTX. Third, molecular-dynamic simulations show that the observed changes create a novel chemical and physical topology consistent with increased enzyme catalysis. Finally, we show that a toxic serine protease from the Mexican beaded lizard (GTX) [2] has evolved convergently through almost identical functional changes. Together, these results suggest that the evolution of toxicity might be predictable-arising via adaptive structural modification of analogous labile regulatory loops of an ancestral serine protease-and thus might aid in the identification of other toxic proteins.