Molecular mechanism of CFTR channel gating: transmission of conformational signals originating at the catalytic site

CFTR通道门控的分子机制：源自催化位点的构象信号的传输

• 批准号: G0501200/1
• 负责人: Paola Vergani
• 金额: $ 39.68万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0501200%2F1
• 关键词: Molecular; mechanism; CFTR; channel; gating

Cystic fibrosis is the most common life-threatening inherited disease in the UK. The disease is caused by absence or malfunction of a protein called CFTR. CFTR is a channel protein: a specialized machine that allows movement of ions into and out of cells. It consists of several parts, or domains. One part, the transmembrane domain, is embedded in the cells’ membrane and forms a pore, a pathway through which the ions can flow. A molecule called ATP remotely controls access to the pore by binding to CFTR at its nucleotide-binding domains (or NBDs). What shape changes occur in the NBDs when ATP binds or when it is cleaved? How are these shape changes transmitted to the transmembrane domain, where the pore opens or closes? Answering these basic questions could suggest new ways of treating some cystic fibrosis patients. Many other proteins, related to CFTR, have NBDs. We will use the evolutionary record of this family, as well as sensitive recordings of tiny electrical signals generated by CFTR molecules, to probe the general mechanism by which NBDs drive the changes in shape of adjacent domains -- in CFTR itself and in other, harder to investigate, members of the same protein family.

囊性纤维化是英国最常见的威胁生命的遗传病。这种疾病是由一种名为cftr的蛋白质缺失或功能障碍引起的。Cftr是一种通道蛋白：一种特殊的机器，允许离子进出细胞。它由几个部分或域组成。其中一个部分，跨膜结构域，嵌入细胞膜并形成一个孔，离子可以通过这个孔流动。一种名为ATP的分子通过与其核苷酸结合域(或NbD)上的CFTR结合来远程控制进入毛孔的途径。当ATP结合或切割时，NBD中会发生什么形状的变化？这些形状变化是如何传递到跨膜区的，在那里孔是打开或关闭的？回答这些基本问题可能会为治疗一些囊性纤维化患者提供新的方法。与cftr相关的许多其他蛋白质都有NBD。我们将使用该家族的进化记录，以及CFTR分子产生的微小电信号的敏感记录，来探索NBD驱动相邻结构域形状变化的一般机制-在CFTR本身和同一蛋白质家族中其他更难研究的成员中。