Department of Molecular Biophysics and Biochemistry, Yale University, 266 Whitney Avenue, New Haven, CT 06520, USA.
J Mol Biol. 2011 Apr 22;408(1):9-17. doi: 10.1016/j.jmb.2011.02.033. Epub 2011 Feb 23.
Hookworms are human parasites that have devastating effects on global health, particularly in underdeveloped countries. Ancylostoma ceylanicum infects humans and animals, making it a useful model organism to study disease pathogenesis. A. ceylanicum excretory-secretory protein 2 (AceES-2), a highly immunoreactive molecule secreted by adult worms at the site of intestinal attachment, is partially protective when administered as a mucosal vaccine against hookworm anemia. The crystal structure of AceES-2 determined at 1.75 Å resolution shows that it adopts a netrin-like fold similar to that found in tissue inhibitors of matrix metalloproteases (TIMPs) and in complement factors C3 and C5. However, recombinant AceES-2 does not significantly inhibit the 10 most abundant human matrix metalloproteases or complement-mediated cell lysis. The presence of a highly acidic surface on AceES-2 suggests that it may function as a cytokine decoy receptor. Several small nematode proteins that have been annotated as TIMPs or netrin-domain-containing proteins display sequence homology in structurally important regions of AceES-2's netrin-like fold. Together, our results suggest that AceES-2 defines a novel family of nematode netrin-like proteins, which may function to modulate the host immune response to hookworm and other parasites.
钩虫是一种对全球健康造成严重影响的人类寄生虫，特别是在欠发达国家。旋毛虫感染人类和动物，使其成为研究疾病发病机制的有用模式生物。旋毛虫排泄分泌蛋白 2（AceES-2）是一种高度免疫原性的分子，由肠道附着部位的成虫分泌，作为黏膜疫苗接种时对钩虫性贫血具有部分保护作用。在 1.75Å分辨率下确定的 AceES-2 晶体结构表明，它采用类似于基质金属蛋白酶组织抑制剂（TIMPs）和补体因子 C3 和 C5 的 netrin 样折叠。然而，重组 AceES-2 并不能显著抑制 10 种最丰富的人类基质金属蛋白酶或补体介导的细胞裂解。AceES-2 表面高度酸性的存在表明它可能作为细胞因子诱饵受体发挥作用。一些被注释为 TIMPs 或 netrin 结构域蛋白的小线虫蛋白在 AceES-2 的 netrin 样折叠的结构重要区域显示出序列同源性。总之，我们的结果表明 AceES-2 定义了一类新的线虫 netrin 样蛋白，可能在调节宿主对钩虫和其他寄生虫的免疫反应中发挥作用。
