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

囊性纤维化是英国最常见的危及生命的遗传性疾病。这种疾病是由一种叫做CFTR的蛋白质缺失或功能障碍引起的。CFTR是一种通道蛋白：一种允许离子进出细胞的专用机器。它由几个部分或域组成。其中一部分是跨膜结构域，嵌入细胞膜并形成一个孔，这是离子可以流动的途径。一种叫做ATP的分子通过与CFTR的核苷酸结合域（nbd）结合来远程控制进入孔的通道。当ATP结合或断裂时，nbd会发生什么形状的变化？这些形状的变化是如何传递到跨膜区域的，即孔打开或关闭的地方？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。许多其他与CFTR相关的蛋白质都有nbd。我们将利用这个家族的进化记录，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本身和其他更难研究的相同蛋白质家族成员中。

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.