Cystic fibrosis transmembrane conductance regulator mutations that disrupt nucleotide binding.
Cystic fibrosis transmembrane conductance regulator mutations that disrupt nucleotide binding.
复制标题
囊性纤维化跨膜电导调节因子突变会破坏核苷酸结合。
DOI：
10.1172/jci117311
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发表时间：
1994
期刊：
影响因子：
--
通讯作者：
Sorscher,EJ
中科院分区：
文献类型：
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作者：
Logan,J;Hiestand,D;Daram,P;Huang,Z;Muccio,DD;Hartman,J;Haley,B;Cook,WJ;Sorscher,EJ
越来越多的证据表明囊性纤维化（CF）的分子发病机制存在异质性。例如，囊性纤维化跨膜电导调节因子 (CFTR) 内 508 位苯丙氨酸 (delta F508) 的缺失等突变似乎会通过破坏正常的生物合成加工而导致疾病，这是一种导致突变蛋白在内质网内滞留和降解的机制。其他突变，例如 CFTR 551 位上相对常见的甘氨酸-->天冬氨酸替换 (G551D) 似乎是正常加工的，因此必须通过某种其他机制引起疾病。由于 delta F508 和 G551D 均发生在 CFTR 的预测核苷酸结合域 (NBD) 内，因此我们测试了这些突变对蛋白质核苷酸结合的影响。我们发现 G551D 和 CFTR 第二核苷酸结合结构域中的相应突变 G1349D 导致 CFTR NBD 的核苷酸结合减少，而 delta F508 突变不会改变核苷酸结合。这些结果暗示 ATP 结合缺陷是导致 CF 的相对常见突变的致病机制的原因之一，并表明 30 多个原核和真核核苷酸结合域中存在的高度保守区域的结构完整性可能对正常核苷酸结合至关重要。
Increasing evidence suggests heterogeneity in the molecular pathogenesis of cystic fibrosis (CF). Mutations such as deletion of phenylalanine at position 508 (delta F508) within the cystic fibrosis transmembrane conductance regulator (CFTR), for example, appear to cause disease by abrogating normal biosynthetic processing, a mechanism which results in retention and degradation of the mutant protein within the endoplasmic reticulum. Other mutations, such as the relatively common glycine-->aspartic acid replacement at CFTR position 551 (G551D) appear to be normally processed, and therefore must cause disease through some other mechanism. Because delta F508 and G551D both occur within a predicted nucleotide binding domain (NBD) of the CFTR, we tested the influence of these mutations on nucleotide binding by the protein. We found that G551D and the corresponding mutation in the CFTR second nucleotide binding domain, G1349D, led to decreased nucleotide binding by CFTR NBDs, while the delta F508 mutation did not alter nucleotide binding. These results implicate defective ATP binding as contributing to the pathogenic mechanism of a relatively common mutation leading to CF, and suggest that structural integrity of a highly conserved region present in over 30 prokaryotic and eukaryotic nucleotide binding domains may be critical for normal nucleotide binding.Images