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Abstract：
Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a pivotal immune checkpoint receptor, playing a crucial role in modulating T-cell activation. In this study, we delved into the underlying mechanism by which a common mutation, G199R, in the cytoplasmic domain of CTLA-4 impacts its inhibitory function. Utilizing nuclear magnetic resonance (NMR) spectroscopy and biochemical techniques, we mapped the conformational changes induced by this mutation and investigated its role in CTLA-4 activity. Our findings reveal that this mutation leads to a distinct conformational alteration, enhancing protein-membrane interactions. Moreover, functional assays demonstrated an improved capacity of the G199R mutant to downregulate T-cell activation, underscoring its potential role in immune-related disorders. These results not only enhance our understanding of CTLA-4 regulatory mechanisms but also provide insights for targeted therapeutic strategies addressing immune dysregulation linked to CTLA-4 mutations.
摘要：
细胞毒性T淋巴细胞抗原4（CTLA-4）是一种关键的免疫检查点受体，在调节T细胞活化中起着至关重要的作用。在这项研究中,我们深入研究了常见突变的潜在机制，G199R,在CTLA-4的细胞质结构域中影响其抑制功能。利用核磁共振（NMR）光谱和生化技术，我们绘制了该突变诱导的构象变化，并研究了其在CTLA-4活性中的作用。我们的发现表明，这种突变会导致明显的构象改变，增强蛋白质-膜相互作用。此外，功能测定表明G199R突变体下调T细胞活化的能力提高，强调其在免疫相关疾病中的潜在作用。这些结果不仅增强了我们对CTLA-4调节机制的理解，而且为解决与CTLA-4突变相关的免疫失调的靶向治疗策略提供了见解。
