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J. Biol. Chem., Vol. 280, Issue 22, 21115-21121, June 3, 2005

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Defining a Minimal Motif Required to Prevent Connexin Oligomerization in the Endoplasmic Reticulum^*

Jose Maza, Jayasri Das Sarma, and Michael Koval

From the Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

In contrast to most multimeric transmembrane complexes that oligomerize in the endoplasmic reticulum (ER), the gap junction protein connexin43 (Cx43) oligomerizes in an aspect of the Golgi apparatus. The mechanisms that prevent oligomerization of Cx43 and related connexins in the ER are not well understood. Also, some studies suggest that connexins can oligomerize in the ER. We used connexin constructs containing a C-terminal dilysine-based ER retention/retrieval signal (HKKSL) transfected into HeLa cells to study early events in connexin oligomerization. Using this approach, Cx43-HKKSL was retained in the ER and prevented from oligomerization. However, another ER-retained HKKSL-tagged connexin, Cx32-HKKSL, had the capacity to oligomerize. Because this suggested that Cx43 contains a motif that prevented oligomerization in the ER, a series of HKKSL-tagged and untagged Cx32/Cx43 chimeras was screened to define this motif. The minimal motif, which prevented ER oligomerization, consisted of the complete third transmembrane domain and the second extracellular loop from Cx43 on a Cx32 backbone. We propose that charged residues present in Cx43 and related connexins help prevent ER oligomerization by stabilizing the third transmembrane domain in the membrane bilayer.

Received for publication, November 8, 2004 , and in revised form, March 14, 2005.

^* This work was supported by National Institutes of Health Grants GM61012 and P01-HL019737-26, Project 3 (to M. K.). 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.

Present address: Dept. of Neurology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107.

To whom correspondence should be addressed: Emory University School of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Whitehead Biomedical Research Bldg., 615 Michael St., Suite 205M, Atlanta, GA 30322.

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