Phartiyal Pallavi, Jones Eugenia M C, Robertson Gail A
Department of Physiology, University of Wisconsin, Madison, Wisconsin 53711; Cellular and Molecular Biology Program, University of Wisconsin, Madison, Wisconsin 53711.
Department of Physiology, University of Wisconsin, Madison, Wisconsin 53711.
J Biol Chem. 2007 Mar 30;282(13):9874-9882. doi: 10.1074/jbc.M610875200. Epub 2007 Feb 1.
Alternate transcripts of the human ether-à-go-go-related gene (hERG1) encode two subunits, hERG 1a and 1b, which form potassium channels regulating cardiac repolarization, neuronal firing frequency, and neoplastic cell growth. The 1a and 1b subunits are identical except for their unique, cytoplasmic N termini, and they readily co-assemble in heterologous and native systems. We tested the hypothesis that interactions of nascent N termini promote heteromeric assembly of 1a and 1b subunits. We found that 1a and 1b N-terminal fragments bind in a direct and dose-dependent manner. hERG1 hetero-oligomerization occurs in the endoplasmic reticulum where co-expression of N-terminal fragments with hERG1 subunits disrupted oligomerization and core glycosylation. The disruption of core glycosylation, a cotranslational event, allows us to pinpoint these N-terminal interactions to the earliest steps in biogenesis. Thus, N-terminal interactions mediate hERG 1a/1b assembly, a process whose perturbation may represent a new mechanism for disease.
人类醚 - 去极化相关基因（hERG1）的可变转录本编码两个亚基，即hERG 1a和1b，它们形成调节心脏复极化、神经元放电频率和肿瘤细胞生长的钾通道。1a和1b亚基除了其独特的胞质N末端外完全相同，并且它们很容易在异源和天然系统中共同组装。我们测试了新生N末端的相互作用促进1a和1b亚基异源组装的假说。我们发现1a和1b的N末端片段以直接且剂量依赖性的方式结合。hERG1异源寡聚化发生在内质网中，其中N末端片段与hERG1亚基的共表达破坏了寡聚化和核心糖基化。核心糖基化是一个共翻译事件，其破坏使我们能够将这些N末端相互作用定位到生物发生的最早步骤。因此，N末端相互作用介导hERG 1a/1b组装，这一过程的扰动可能代表一种新的疾病机制。
