对TGF-B信号通路中断的分子洞察力,由COPD中非同义SNP变体引起的:一种在和分子动力学模拟研究
Nidhi Mahajan1, Sidhartha Singh2, Vishal Chopra3
1Department of Biotechnology, Thapar Institute of Engineering & Technology, Patiala, India.
Journal of biomolecular structure & dynamics
|October 14, 2025
概括
转化生长因子β (TGF-B) 信号的遗传变异会影响血管健康. 这项研究在关键基因中发现了42种有害的nsSNP,揭示了这些突变如何破坏TGF-B信号传递,并导致肺高血压和COPD等疾病.
科学领域:
- 遗传学和分子生物学
- 心血管研究研究心血管研究
- 肺部医学 肺部医学
背景情况:
- 转化生长因子β (TGF-B) 信号传递对于血管平衡和肺重塑至关重要.
- 干扰TGF-B信号传递与肺高血压 (PH) 和慢性阻塞性肺病 (COPD) 有关.
- 在TGF-B通路基因中的非同义单核酸多态 (nsSNP) 可以改变蛋白质功能和疾病风险.
研究的目的:
- 在TGF-B信号级联中的关键基因内计算识别和表征有害的nsSNP.
- 研究这些nsSNP对蛋白质稳定性和相互作用的结构和功能影响.
- 探索这些遗传变异在PH相关的COPD病变发生过程中的潜在作用.
主要方法:
- 使用多种预测工具 (SIFT,PolyPhen2,CADD,REVEL等) 分析TGFB1,TGFBR1,TGFBR2,SMAD2,SMAD3和SMAD4中的nsSNP. ) 的情况.
- 进化保护 (ConSurf) 和物理化学变化 (ProtParam) 的评估.
- 产生和验证蛋白质结构模型 (I-TASSER,Ramachandran图),然后进行蛋白质-蛋白质对接和分子动力学 (MD) 模拟.
主要成果:
- 在六个分析的基因中确定了42个高可信度有害的nsSNP.
- 特定的变异 (例如,TGFB中的R156C,TGFBRII中的N384S) 显示出对蛋白质构成的显著破坏稳定的影响.
- 发现TGFB中的E313D变体诱导了结构紧缩,可能会损害信号传导.
结论:
- 在TGF-B信号组件中有害的nsSNP可能会损害蛋白质的稳定性并破坏通路通信.
- 这些遗传变化可能有助于PH相关的COPD的发病.
- 已识别的nsSNP代表了未来治疗干预的潜在目标.
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