Department of Biological Science, Florida State University, Tallahassee, FL.
Department of Biology, University of Central Florida, Orlando, FL.
Mol Biol Evol. 2018 Apr 1;35(4):887-898. doi: 10.1093/molbev/msx334.
Evolutionary innovations and complex phenotypes seemingly require an improbable amount of genetic change to evolve. Rattlesnakes display two dramatically different venom phenotypes. Type I venoms are hemorrhagic with low systemic toxicity and high expression of tissue-destroying snake venom metalloproteinases. Type II venoms are highly neurotoxic and lack snake venom metalloproteinase expression and associated hemorrhagic activity. This dichotomy hinges on Mojave toxin (MTx), a phospholipase A2 (PLA2) based β-neurotoxin expressed in Type II venoms. MTx is comprised of a nontoxic acidic subunit that undergoes extensive proteolytic processing and allosterically regulates activity of a neurotoxic basic subunit. Evolution of the acidic subunit presents an evolutionary challenge because the need for high expression of a nontoxic venom component and the proteolytic machinery required for processing suggests genetic changes of seemingly little immediate benefit to fitness. We showed that MTx evolved through a cascading series of exaptations unlocked by a single nucleotide change. The evolution of one new cleavage site in the acidic subunit unmasked buried cleavage sites already present in ancestral PLA2s, enabling proteolytic processing. Snake venom serine proteases, already present in the venom to disrupt prey hemostasis, possess the requisite specificities for MTx acidic subunit proteolysis. The dimerization interface between MTx subunits evolved by exploiting a latent, but masked, hydrophobic interaction between ancestral PLA2s. The evolution of MTx through exaptation of existing functional and structural features suggests complex phenotypes that depend on evolutionary innovations can arise from minimal genetic change enabled by prior evolution.
进化创新和复杂表型似乎需要大量的遗传变化才能进化。响尾蛇表现出两种截然不同的毒液表型。I 型毒液具有低系统性毒性和高组织破坏性蛇毒金属蛋白酶表达的出血性。II 型毒液具有高度神经毒性，缺乏蛇毒金属蛋白酶表达和相关的出血活性。这种二分法取决于莫哈韦毒素（MTx），这是一种在 II 型毒液中表达的基于磷脂酶 A2（PLA2）的β神经毒素。MTx 由非毒性酸性亚基组成，该亚基经历广泛的蛋白水解加工，并变构调节神经毒性碱性亚基的活性。酸性亚基的进化提出了一个进化挑战，因为需要高表达一种非毒性毒液成分和进行加工所需的蛋白水解机制表明，遗传变化似乎对适应性没有直接的好处。我们表明，MTx 通过单个核苷酸变化解锁的级联系列适应进化而来。酸性亚基中新的切割位点的进化揭示了在祖 PLA2 中已经存在的埋藏切割位点，从而能够进行蛋白水解加工。蛇毒丝氨酸蛋白酶已经存在于毒液中以破坏猎物的止血功能，它们具有 MTx 酸性亚基蛋白水解所需的特异性。MTx 亚基之间的二聚化界面通过利用祖 PLA2 之间潜在但被掩盖的疏水相互作用进化而来。通过利用现有功能和结构特征的适应进化而来的 MTx 表明，依赖于进化创新的复杂表型可以通过先前的进化产生的最小遗传变化来实现。
