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J. Biol. Chem., Vol. 282, Issue 45, 33201-33209, November 9, 2007

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Mutations in the Sec61p Channel Affecting Signal Sequence Recognition and Membrane Protein Topology^*

From the Biozentrum, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland

The orientation of most single-spanning membrane proteins obeys the "positive-inside rule", i.e. the flanking region of the transmembrane segment that is more positively charged remains in the cytosol. These membrane proteins are integrated by the Sec61/SecY translocon, but how their orientation is achieved is unknown. We have screened for mutations in yeast Sec61p that alter the orientation of single-spanning membrane proteins. We identified a class of mutants that are less efficient in retaining the positively charged flanking region in the cytosol. Surprisingly, these mutations are located at many different sites in the Sec61/SecY molecule, and they do not only involve charged amino acid residues. All these mutants have a prl phenotype that so far have only been seen in bacteria; they allow proteins with defective signal sequences to be translocated, likely because the Sec61p channel opens more easily. A similar correlation between topology defects and prl phenotype was also seen with previously identified yeast Sec61 mutants. Our results suggest a model in which the regulated opening of the translocon is required for the faithful orientation of membrane proteins.

Received for publication, August 28, 2007

^* This work was supported by Grant 3100A0-109424/1 from the Swiss National Science Foundation. 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.

¹ Present address: Harvard Medical School, Dept. of Cell Biology, 240 Long-wood Ave., Boston, MA 02115.

² To whom correspondence should be addressed: Biozentrum, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland. Tel.: 41-61-2672164; Fax: 41-61-2672148; E-mail: Martin.Spiess{at}unibas.ch.

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				M. Lerch-Bader, C. Lundin, H. Kim, I. Nilsson, and G. von Heijne Contribution of positively charged flanking residues to the insertion of transmembrane helices into the endoplasmic reticulum PNAS, March 18, 2008; 105(11): 4127 - 4132. [Abstract] [Full Text] [PDF]