The CFTR Interactome

项目总结 囊性纤维化是最常见的儿童遗传性疾病之一，影响 1：4000名在美国出生的儿童(www.cff.org)。的主要突破之一 分子医学是由弗朗西斯·柯林斯等人发现的。在1988年，这项事业 对于超过70%的患者来说，CF是单一的基因突变，框内缺失 囊性纤维化跨膜电导调节基因中的苯丙氨酸508 (DeltaF508 CFTR)。与野生型cftr相比，突变的∆F508cftr阴离子 通道发生错误折叠，显示构象缺陷，几乎没有 活动。近年来的大量研究表明，构象缺陷导致了 F508缺失不仅影响蛋白质功能，而且在很大程度上也影响蛋白质 相互作用和翻译后修改(PTM)，以及 这些相互作用的特异性和亲和力可能会导致这种疾病。因此，巨大的 人们正在努力开发新的化合物来纠正构象 缺陷，但它们受到以下事实的阻碍：∆F508CFTR的构象缺陷 还没有得到充分的描述。通过开发新的方法来实现 蛋白质活体结构的质谱学表征，后研究 影响蛋白质构象的CFTR的翻译修饰，以及 开发识别构象特异性相互作用的方法，我们的目标是 有助于更好地了解Cf的构象缺陷及其影响 关于这种疾病中的蛋白质-蛋白质相互作用。

Project summary Cystic Fibrosis (CF) is one of the most common inherited childhood diseases, impacting 1:4,000 children born in the US (www.cff.org). One of the major breakthroughs in molecular medicine was the discovery by Francis Collins et al. in 1988, that the cause for CF in over 70% of patients was a single genetic mutation, an in-frame deletion of Phenylalanine 508 in the Cystic Fibrosis transmembrane conductance regulator gene (DeltaF508 CFTR). In contrast to wild type CFTR, the mutated ∆F508 CFTR anion channel becomes misfolded, displays a conformational defect, and has little to no activity. Intense research in recent years indicates that the conformational defect caused by the F508 deletion not only impacts protein function, but to a major extent also protein interactions and post-translational modifications (PTMs), and that changes in the specificity and affinity of these interactions may drive the disease. Therefore, huge efforts are being made to develop new compounds that correct the conformational defect, but they are hampered by the fact that the conformational defect of ∆F508 CFTR has not yet been fully characterized. Through the development of novel methods for in vivo structural characterization of proteins by mass spectrometry, investigation of post- translational modifications of CFTR, which influence protein conformation, and development of methods for identification of conformation-specific interactions, we aim to contribute to a better understanding of the conformational defect in CF and its impact on protein-protein interactions in this disease.