结构洞察力揭示了LAG-3同位体化,带结合和功能之间的相互作用
John L Silberstein1,2, Jasper Du3, Kun-Wei Chan4
1Program in Immunology, Stanford University School of Medicine, Stanford, CA 94305.
概括
淋巴细胞激活基因-3 (LAG-3) 通过域2进行二分化对于其抑制功能至关重要. 准LAG-3域可以阻止连接体结合,并提供新的免疫疗法策略.
科学领域:
- 免疫学 免疫学 免疫学
- 结构生物学 结构生物学
- 癌症免疫疗法癌症免疫疗法
背景情况:
- 淋巴细胞激活基因-3 (LAG-3) 是T细胞上的抑制受体,也是免疫治疗的关键标.
- 据认为,LAG-3的Domain 1 (D1) 是与MHCII和FGL1配体的主要相互作用部位.
研究的目的:
- 阐明LAG-3功能的结构基础,并确定新的治疗点.
- 调查LAG-3二分化对其抑制活性和连接体结合的作用.
主要方法:
- 高分辨率的结构分析的糖化小鼠LAG-3ectodomain.
- 局部定向的突变发生来破坏二元化接口.
- 生物化学测试以评估连体结合 (MHCII,FGL1) 和T细胞抑制.
主要成果:
- 通过Domain 2 (D2),LAG-3经历了 cis-homodimerization,这对其功能至关重要.
- 在二元接口中,一种新的蛋白质-甘氨酸相互作用影响了D1的方向.
- 突变破坏D2二分化,取消了连接体结合和T细胞抑制.
- 针对D1,D2和D3域的抗体阻断了二分化和配体结合,表明了全调节.
结论:
- 由D2调节的LAG-3二分化对其抑制功能和连接体相互作用至关重要.
- 超出D1的新型表征可以作为开发基于LAG-3的免疫疗法的目标.
- 了解LAG-3的结构和二元化为癌症治疗提供了新的途径.
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