rLZ-8诱导SGC-7901胃癌细胞自噬依赖性细胞死亡功能结构域的研究

The discovery and recognition of a new functional protein activity domain has become a hot topic in the field of anticancer drug research. To investigate the relationship between Functional domain and anti-tumor activity has realistic value to elucidate the molecular mechanisms of complex physiological processes induced by anticancer drugs..In a similar study, we have first identified and described rLZ-8's crystal structure determination, but also found that rLZ-8 induced an autophage-dependent cell death in gastric cancer cell line SGC-7901.Compare to FIP-fve structure which is highly homologous sequence with LZ-8, but not has anti-tumor activity, we infer some new anti-tumor domains on rLZ-8 structure. Means of molecular biology, cell biology and cellular chemistry will be applied to the corresponding protein structure mutation and functional conformation. The aim of the project is to explore the relationship between that rLZ-8 characteristic domain of anti-tumor function, and ultimately to clarify rLZ-8's anti-tumor domains.

发现和确认新功能性蛋白活性结构区域已成为抗肿瘤药物研究领域引人关注的活跃前沿。其中功能性结构区域与其杀伤肿瘤相互作用关系的研究，对阐明抗肿瘤药物所诱导的复杂生理过程中的分子机制具有现实意义。在国际同类研究中，我们率先完成了免疫调节蛋白rLZ-8晶体结构的测定和解析工作，同时也发现了rLZ-8诱导胃癌细胞SGC-7901发生自噬依赖性性细胞死亡的新功能。通过将rLZ-8与其序列高度同源而不具有抗肿瘤活性的FIP-fve晶体结构进行比对分析，我们推断出rLZ-8结构中可能与新功能相关的系列位点，再利用分子生物学、细胞生物学和细胞化学手段进行相应的蛋白质结构位点突变及功能验证,目的是探讨rLZ-8特征性结构域与抗肿瘤功能的相互关系，最终阐明rLZ-8蛋白的抗肿瘤功能结构域。

本项目通过对rLZ-8晶体结构特征的分析及其与不具有抗肿瘤活性且在氨基酸序列上高度同源的FIP-fve晶体结构的比对，再利用分子生物学、细胞生物学和生物信息学手段进行相应的蛋白质结构位点突变及功能验证，揭示了rLZ-8特征性结构域与抗肿瘤功能的相互关系，最终阐明了rLZ-8蛋白具有抗肿瘤功能的结构特征，为接续的rLZ-8抗肿瘤药物药效学及免疫调节机制的深入研究提供有利的结构生物学依据。