由肉毒神经毒素A复合体破坏E-cadherin粘附的分子基础
Kwangkook Lee1, Xiaofen Zhong2, Shenyan Gu1
1Department of Physiology and Biophysics, University of California, Irvine, CA 92697, USA.
概括
肉毒神经毒素 (BoNT/A) 通过结合E-cadherin和碳水化合物的血凝素 (HA) 穿过肠道屏障. 这种相互作用会损害细胞结,使毒素吸收和口服毒性成为可能.
科学领域:
- 分子生物学分子生物学
- 结构生物学是结构生物学.
- 微生物学 微生物学
背景情况:
- 肉毒神经毒素 (BoNT) 在食物传播肉毒症中穿越肠道屏障的机制尚不清楚.
- 玻尿酸毒素是一种由Clostridium botulinum细菌产生的强有力的神经毒素.
研究的目的:
- 阐明BoNT/A的血凝素 (HA) 促进肠道吸收的分子机制.
- 确定HA与宿主细胞相互作用的结构基础.
主要方法:
- 进行X射线晶体学以确定与E-cadherin结合的BoNT/A HA复合物的结构.
- 完整的BoNT/A复合物的重组生产.
- 在小鼠模型中进行体内口服毒性测定.
主要成果:
- 晶体结构揭示了HA复合物与E-cadherin和细胞表面碳水化合物的特定结合.
- 对E-cadherin的HA结合将其隔离到单质状态,破坏细胞间连接.
- 破坏HA的E-cadherin或碳水化合物结合显著降低了BoNT/A的体内口服毒性.
结论:
- 博恩特/AHA复合物利用双结合 (E-cadherin和碳水化合物) 突破肠道上皮屏障.
- 这种分子机制解释了HA如何促进BoNT/A的口服毒性,为治疗干预提供了目标.
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