Heteromeric assembly of human ether-à-go-go-related gene (hERG) 1a/1b channels occurs cotranslationally via N-terminal interactions

J Biol Chem. 2007 Mar 30;282(13):9874-82. doi: 10.1074/jbc.M610875200. Epub 2007 Feb 1.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Ether-A-Go-Go Potassium Channels / biosynthesis
  • Ether-A-Go-Go Potassium Channels / genetics*
  • Ether-A-Go-Go Potassium Channels / metabolism
  • Glycosylation
  • Humans
  • Peptide Fragments / biosynthesis
  • Peptide Fragments / genetics*
  • Peptide Fragments / metabolism
  • Protein Biosynthesis / physiology*
  • Protein Processing, Post-Translational
  • Protein Structure, Tertiary / genetics
  • Protein Subunits / biosynthesis
  • Protein Subunits / genetics*
  • Protein Subunits / metabolism

Substances

  • Ether-A-Go-Go Potassium Channels
  • Peptide Fragments
  • Protein Subunits