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危及生命的遗传性疾病，这种疾病是由一种称为 CFTR 的蛋白质缺失或功能障碍引起的，CFTR 是一种通道蛋白：一种允许离子进出细胞的特殊机器。跨膜结构域由多个部分或结构域组成，嵌入细胞膜中并形成一个孔，离子可以通过该通道流动，通过与 ATP 结合来远程控制进入孔的通道。当 ATP 结合或裂解时，CFTR 的核苷酸结合域（或 NBD）会发生什么形状变化？回答这些基本问题？可能会提出治疗一些囊性纤维化患者的新方法。许多其他与 CFTR 相关的蛋白质都具有 NBD，我们将使用该家族的进化记录以及所产生的微小电信号的敏感记录。通过 CFTR 分子，探究 NBD 驱动相邻结构域形状变化的一般机制 - 在 CFTR 本身以及其他更难研究的同一蛋白质家族成员中。