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J. Biol. Chem., Vol. 279, Issue 53, 55283-55289, December 31, 2004

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Direct Comparison of the Functional Roles Played by Different Transmembrane Regions in the Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channel Pore^*

Ning Ge, Chantal N. Muise, Xiandi Gong, and Paul Linsdell¶

From the Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia B3H 1X5, Canada

The cystic fibrosis transmembrane conductance regulator (CFTR) Cl^– channel contains 12 transmembrane (TM) regions that are presumed to form the channel pore. However, little is known about the relative functional contribution of different TM regions to the pore. We have used patch clamp recording to investigate the functional consequences of point mutations throughout the six transmembrane regions in the N-terminal part of the CFTR protein (TM1-TM6). A range of specific functional assays compared the single channel conductance, anion binding, and anion selectivity properties of different channel variants. Overall, our results suggest that TM1 and -6 play dominant roles in forming the channel pore and determining its functional properties, with TM5 perhaps playing a lesser role. In contrast, TM2, -3, and -4 appear to play only minor supporting roles. These results define transmembrane regions 1 and 6 as major contributors to the CFTR channel pore and have strong implications for emerging structural models of CFTR and related ATP-binding cassette proteins.

Received for publication, October 20, 2004

^* This work was supported in part by the Canadian Institutes of Health Research. 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.

Supported by the Karen Lackey summer studentship award from the Canadian Cystic Fibrosis Foundation.

Present address: School of Biological Sciences, Nanyang Technological University, Singapore 637551.

^¶ To whom correspondence should be addressed. Tel.: 902-494-2265; Fax: 902-494-1685; E-mail: paul.linsdell{at}dal.ca.

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