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J. Biol. Chem., Vol. 281, Issue 39, 28958-28963, September 29, 2006

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The Structural Context of Disease-causing Mutations in Gap Junctions^*

Sarel J. Fleishman¹², Adi D. Sabag¹, Eran Ophir, Karen B. Avraham, and Nir Ben-Tal³

From the Department of Biochemistry, George S. Wise Faculty of Life Sciences, and Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel-Aviv University, 69978 Ramat Aviv, Israel

Gap junctions form intercellular channels that mediate metabolic and electrical signaling between neighboring cells in a tissue. Lack of an atomic resolution structure of the gap junction has made it difficult to identify interactions that stabilize its transmembrane domain. Using a recently computed model of this domain, which specifies the locations of each amino acid, we postulated the existence of several interactions and tested them experimentally. We introduced mutations within the transmembrane domain of the gap junction-forming protein connexin that were previously implicated in genetic diseases and that apparently destabilized the gap junction, as evidenced here by the absence of the protein from the sites of cell-cell apposition. The model structure helped identify positions on adjacent helices where second-site mutations restored membrane localization, revealing possible interactions between residue pairs. We thus identified two putative salt bridges and one pair involved in packing interactions in which one disease-causing mutation suppressed the effects of another. These results seem to reveal some of the physical forces that underlie the structural stability of the gap junction transmembrane domain and suggest that abrogation of such interactions bring about some of the effects of disease-causing mutations.

Received for publication, June 15, 2006

^* This work was supported by the European Commission FP6 Integrated Project EUROHEAR, LSHG-CT-20054-512063, Israel Science Foundation Grant 222/04, and National Institutes of Health Grant R01 DC005641. 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 data.

¹ These authors contributed equally to this work.

² Supported by a doctoral fellowship from the Clore Israel Foundation.

³ To whom correspondence should be addressed. Tel.: 972-3-640-6624; Fax: 972-3-640-6834; E-mail: nirb{at}tauex.tau.ac.il.

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