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疾病。该疾病是由称为CFTR的蛋白质缺失或故障引起的。 CFTR是一种通道蛋白：一种专门的机器，可将离子移入和流入细胞。它由几个部分或域组成。跨膜结构域的一部分嵌入细胞膜中并形成孔，这是一个离子可以流动的途径。一个称为ATP的分子通过与CFTR结合在其核犹他州结合域（或NBD）来远程控制对孔的访问。当ATP绑定或清除时，NBD中会发生什么形状变化？这些形状的变化如何传输到孔打开或关闭的跨膜结构域？回答这些基本问题可能会暗示治疗某些囊性纤维化患者的新方法。与CFTR有关的许多其他蛋白质具有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测NBDS在CFTR本身和其他更难研究同一蛋白质家族成员的CFTR本身中，NBDS驱动相邻域形状的变化的一般机制。