通过对进化序列的分析揭示了 ΔF508 CFTR 有效校正的要求
Juan L Mendoza1, André Schmidt, Qin Li
1Molecular Biophysics Program, and Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9040, USA.
Cell
|January 24, 2012
概括
囊性纤维化转膜导电调节器 (CFTR) 的错误折叠是一个关键问题. 纠正NBD1和ICL4相互作用中的两个折叠缺陷将CFTR功能恢复到野生类型水平.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 遗传学 是一个遗传学.
背景情况:
- 囊性纤维化 (CF) 主要是由囊性纤维化跨膜导电性调节器 (CFTR) 蛋白中 ΔF508 突变的错误折叠引起的.
- F508突变影响第一个核酸结合域 (NBD1) 和它与第四个细胞内循环 (ICL4) 的相互作用.
- 目前针对CFTR折叠缺陷的治疗策略的有效性有限,这表明需要更深入的机制理解.
研究的目的:
- 调查现有的CFTR折叠校正剂化合物的有限疗效的机制基础.
- 为了在CFTR中确定与ΔF508突变统计学上结合的特定位点.
- 评估这些结合位点对NBD1折叠和CFTR-ICL4相互作用的影响.
主要方法:
- 在进化的CFTR序列中分析统计学合的位置.
- 鉴定出突变对NBD1折叠的影响的评估.
- 对突变对NBD1和ICL之间相互作用的影响的评估4.
- 功能性评估CFTR成熟和通道活动.
主要成果:
- F508突变会影响NBD1折叠和NBD1与ICL4.4之间的相互作用.
- 仅纠正NBD1折叠或仅纠正NBD1-ICL4相互作用的策略可以部分挽救 ΔF508 CFTR.
- 结合了解决这两种缺陷的突变,将 ΔF508 CFTR 的成熟度和功能恢复到野生类型的水平.
结论:
- 当前CFTR校正器的有效性有限是由于它们无法解决 ΔF508.8 引起的两种关键折叠缺陷.
- 双重准方法,纠正NBD1折叠和NBD1-ICL4相互作用,是完全恢复功能所必需的.
- 这项研究为开发针对 ΔF508 CFTR 中两种已识别的缺陷的新疗法化合物提供了理由.
相关概念视频
01:49Conserved Binding Sites
Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally analyses the...
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally analyses the...
02:02Cis-regulatory Sequences
Cis-regulatory sequences are short fragments of non-coding DNA that are present on the same chromosomes as the genes that they regulate. These fragments serve as binding sites for transcriptional regulators, proteins that are responsible for controlling gene transcription and differential gene expression across cell types in eukaryotes. Cis-regulatory sequences can be close to the gene of interest or thousands of bases away in the DNA sequence; however, those sequences that are further away are...