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J. Biol. Chem., Vol. 282, Issue 13, 9874-9882, March 30, 2007

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Heteromeric Assembly of Human Ether-à-go-go-related Gene (hERG) 1a/1b Channels Occurs Cotranslationally via N-terminal Interactions^*

Pallavi Phartiyal, Eugenia M. C. Jones, and Gail A. Robertson¹

From the Department of Physiology and Cellular and Molecular Biology Program, University of Wisconsin, Madison, Wisconsin 53711

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.

Received for publication, November 27, 2006 , and in revised form, January 8, 2007.

^* This work was supported in part by National Institutes of Health Grant R01 HL081780 (to G. A. R.) and an American Heart Association Predoctoral Fellowship (to P. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4.

¹ To whom correspondence should be addressed: Dept. of Physiology, University of Wisconsin Satellite Laboratories, 601 Science Dr., Madison, WI 53711. Tel.: 608-265-3339; Fax: 608-265-7821; E-mail: robertson{at}physiology.wisc.edu.

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