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J. Biol. Chem., Vol. 280, Issue 28, 26032-26038, July 15, 2005

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Phospholipids as Determinants of Membrane Protein Topology

PHOSPHATIDYLETHANOLAMINE IS REQUIRED FOR THE PROPER TOPOLOGICAL ORGANIZATION OF THE -AMINOBUTYRIC ACID PERMEASE (GabP) OF ESCHERICHIA COLI^*

Wei Zhang¶, Heidi A. Campbell, Steven C. King||, and William Dowhan**

From the Department of Biochemistry and Molecular Biology, University of Texas-Houston, Medical School and Graduate School of Biomedical Sciences, Houston, Texas, 77030 and the ^||Department of Integrative Biosciences, Oregon Health and Science University, Portland, Oregon 97239

Evidence is accumulating that the topological organization and hence function of some membrane proteins are not solely determined by the amino acid sequence of the protein but are also influenced by the lipid composition of the membrane. The -aminobutyric acid (GABA) permease (GabP) of Escherichia coli has been found in this study to be affected both topologically and kinetically by membrane lipids. Using single cysteine accessibility methods with viable E. coli strains of natural lipid composition and those lacking phosphatidylethanolamine (PE), we have shown that the N-terminal hairpin of GabP is inverted relative to the membrane in PE-lacking cells, with a hinge point in transmembrane domain III. The rate of GABA transport is reduced by more than 99% in PE-lacking cells. The Michaelis constant for GABA transport is not greatly affected nor is the dependence of transport on energy. However, "transport specificity ratio" analysis demonstrated a clear transition state stability difference for GABA and nipecotic acid between the protein in PE-containing and PE-lacking cells. The patterns of observed effects are similar to those seen with the phenylalanine transporter of E. coli (Zhang, W., Bogdanov, M. Pi, J. Pittard, A. J., and Dowhan, W. (2003) J. Biol. Chem. 278, 50128–50135), also an amino acid/polyamine/organocation family member but quite distinct from those observed with lactose permease (Bogdanov, M., Heacock, P. N., and Dowhan, W. (2002) EMBO J. 21, 2107–2116), a major facilitator superfamily member. Therefore, by extending the studies of similarities and differences in lipid responses among and between family groups, we may identify elements within the proteins that facilitate lipid responsiveness.

Received for publication, May 4, 2005

^* This work was supported by Grants GM20487 (to W. D.), GM071128 (to H. A. C.) and NS38226 (to S. C. K.) from the National Institutes of Health. 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.

^¶ Current address: Dept. of Biology, Stanford University, Palo Alto, CA 94305-5430. E-mail: weiz{at}stanford.edu.

^** To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, 6431 Fannin St., Suite 6.200, University of Texas-Houston, Medical School, Houston, TX, 77030. Tel.: 713-500-6051; Fax: 713-500-0652; E-mail: William.Dowhan{at}uth.tmc.edu.

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