Requirements for efficient correction of ΔF508 CFTR revealed by analyses of evolved sequences.
Requirements for efficient correction of ΔF508 CFTR revealed by analyses of evolved sequences.
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DOI：
10.1016/j.cell.2011.11.023
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发表时间：
2012-01-20
期刊：
影响因子：
64.5
通讯作者：
Thomas PJ
中科院分区：
文献类型：
--
作者：
Mendoza JL;Schmidt A;Li Q;Nuvaga E;Barrett T;Bridges RJ;Feranchak AP;Brautigam CA;Thomas PJ
ΔF508 CFTR 的错误折叠是大多数 CF 患者病理的基础。 F508 位于 CFTR 的第一个核苷酸结合域 (NBD1) 中，靠近与第四个细胞内环 (ICL4) 的预测界面。寻找通过纠正折叠缺陷来恢复功能的小分子的努力已经揭示了明显的功效上限。为了了解这一障碍的机制基础，在进化序列中与 508 统计耦合的位置被识别并评估了它们对 NBD1 和 CFTR 折叠的影响。结果表明，ΔF508 突变改变了 NBD1 折叠和与 ICL4 的相互作用，并且对任一单独过程的校正仅部分有效。相比之下，抵消这两种缺陷的突变组合使 ΔF508 的成熟和功能恢复到野生型水平。这些结果为现有校正剂化合物的有限功效提供了机制原理，并提出了识别可校正这两个缺陷步骤的化合物的方法。
Misfolding of ΔF508 CFTR underlies pathology in most CF patients. F508 resides in the first nucleotide binding domain (NBD1) of CFTR near a predicted interface with the fourth intracellular loop (ICL4). Efforts to identify small molecules that restore function by correcting the folding defect have revealed an apparent efficacy ceiling. To understand the mechanistic basis of this obstacle, positions statistically coupled to 508, in evolved sequences, were identified and assessed for their impact on both NBD1 and CFTR folding. The results indicate that both NBD1 folding and interaction with ICL4 are altered by the ΔF508 mutation and that correction of either individual process is only partially effective. By contrast, combination of mutations that counteract both defects restores ΔF508 maturation and function to wild type levels. These results provide a mechanistic rationale for the limited efficacy of extant corrector compounds and suggest approaches for identifying compounds that correct both defective steps.
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