Antimicrobial Functions of Lactoferrin Promote Genetic Conflicts in Ancient Primates and Modern Humans
Antimicrobial Functions of Lactoferrin Promote Genetic Conflicts in Ancient Primates and Modern Humans
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DOI：
10.1371/journal.pgen.1006063
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发表时间：
2016-05-01
期刊：
影响因子：
4.5
通讯作者：
Elde, Nels C.
中科院分区：
文献类型：
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作者：
Barber, Matthew F.;Kronenberg, Zev;Elde, Nels C.
乳铁蛋白是一种多功能哺乳动物免疫蛋白，通过螯合营养铁来限制微生物生长。此外，乳铁蛋白具有直接结合和抑制多种微生物的阳离子蛋白结构域。这些双重功能对乳铁蛋白进化和与微生物的遗传冲突的影响仍不清楚。在这里，我们表明，在灵长类动物分化过程中，乳铁蛋白主要在抗菌肽表面反复经历正选择，这与细菌的长期拮抗作用一致。人类和尼安德特人中丰富的乳铁蛋白多态性也表现出灵长类动物积极选择的特征，将古代宿主微生物冲突与现代人类遗传变异联系起来。乳铁蛋白中快速进化的位点进一步对应于导致脑膜炎、肺炎和败血症的机会性细菌病原体的分子界面。由于微生物主动靶向乳铁蛋白来获取铁，因此我们认为抗菌活性的出现提供了一种关键的适应机制，通过获取新的蛋白质功能引发了进化冲突。
Lactoferrin is a multifunctional mammalian immunity protein that limits microbial growth through sequestration of nutrient iron. Additionally, lactoferrin possesses cationic protein domains that directly bind and inhibit diverse microbes. The implications for these dual functions on lactoferrin evolution and genetic conflicts with microbes remain unclear. Here we show that lactoferrin has been subject to recurrent episodes of positive selection during primate divergence predominately at antimicrobial peptide surfaces consistent with long-term antagonism by bacteria. An abundant lactoferrin polymorphism in human populations and Neanderthals also exhibits signatures of positive selection across primates, linking ancient host-microbe conflicts to modern human genetic variation. Rapidly evolving sites in lactoferrin further correspond to molecular interfaces with opportunistic bacterial pathogens causing meningitis, pneumonia, and sepsis. Because microbes actively target lactoferrin to acquire iron, we propose that the emergence of antimicrobial activity provided a pivotal mechanism of adaptation sparking evolutionary conflicts via acquisition of new protein functions.