A novel CFTR disease-associated mutation causes addition of an extra N-linked oligosaccharide
A novel CFTR disease-associated mutation causes addition of an extra N-linked oligosaccharide
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DOI：
10.1023/a:1010992827511
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发表时间：
2000-01-01
影响因子：
3
通讯作者：
Riordan, JR
中科院分区：
文献类型：
--
作者：
Hämmerle, MM;Aleksandrov, AA;Riordan, JR
我们研究了囊性纤维化患者中检测到的 CFTR 第四胞质外环 (EL4) 中新错义突变的影响。这种取代 (T908N) 创建了一个共有序列 (NX S/T)，用于在 EL4 C 末端附近添加 N 连接寡糖链。如果寡糖基转移酶距膜的距离小于约 12 个氨基酸，则它通常无法访问该共有序列。然而，使用了 T908N 位点，即使它位于预测的膜界面的四个残基内，并且添加的寡糖链与钙连接蛋白（ER 膜的常驻分子伴侣）结合。该变体 CFTR 的氯离子通道活性异常，如 Cl-36(-) 流出率降低和嘈杂的单通道开放状态所证明。这可能反映了 EL4 跨膜序列 C 端的一些位移，因为它包含影响离子孔的残基。
We have examined the influence of a novel missense mutation in the fourth extracytoplasmic loop (EL4) of CFTR detected in a patient with cystic fibrosis. This substitution (T908N) creates a consensus sequence (N X S/T) for addition of an N-linked oligosaccharide chain near the C-terminal end of EL4. Oligosaccharyl transferase generally does not have access to this consensus sequence if it is closer than about twelve amino acids from the membrane. However, the T908N site is used, even though it is within four residues of the predicted membrane interface and the oligosaccharide chain added binds calnexin, a resident chaperone of the ER membrane. The chloride channel activity of this variant CFTR is abnormal as evidenced by a reduced rate of Cl-36(-) efflux and a noisy single channel open state. This may reflect some displacement of the membrane spanning sequence C-terminal of EL4 since it contains residues influencing the ion pore.