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J Biol Chem, Vol. 275, Issue 9, 6207-6213, March 3, 2000

Distant Downstream Sequence Determinants Can Control N-tail Translocation during Protein Insertion into the Endoplasmic Reticulum Membrane^*

IngMarie Nilsson, Susanne Witt^¶, Hans Kiefer^§, Ismael Mingarro^¶, and Gunnar von Heijne

From the Department of Biochemistry, Stockholm University, S-10691 Stockholm, Sweden

We have studied the membrane insertion of ProW, an Escherichia coli inner membrane protein with seven transmembrane segments and a large periplasmic N-terminal tail, into endoplasmic reticulum (ER)-derived dog pancreas microsomes. Strikingly, significant levels of N-tail translocation is seen only when a minimum of four of the transmembrane segments are present; for constructs with fewer transmembrane segments, the N-tail remains mostly nontranslocated and the majority of the molecules adopt an "inverted" topology where normally nontranslocated parts are translocated and vice versa. N-tail translocation can also be promoted by shortening of the N-tail and by the addition of positively charged residues immediately downstream of the first trasnmembrane segment. We conclude that as many as four consecutive transmembrane segments may be collectively involved in determining membrane protein topology in the ER and that the effects of downstream sequence determinants may vary depending on the size and charge of the N-tail. We also provide evidence to suggest that the ProW N-tail is translocated across the ER membrane in a C-to-N-terminal direction.

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^* This work was supported by grants from the Swedish Natural and Technical Sciences Research Councils, the Swedish Cancer Foundation, and the Göran Gustafsson Foundation and by European Commission Grant BIO4-CT96-0129 (to G. v. H.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

^§ Present address: Inst. of Microbiology, University of Hohenheim, Garbenstrasse 30, D-70599 Stuttgart, Germany.

^¶ Present address: Dept. of Biochemistry, University of Valencia, Dr. Moliner 50, E-46100 Burjossot, Valencia, Spain.

To whom correspondence should be addressed. Tel.: 46-8-16-25-90; Fax: 46-8-15-36-79; E-mail: gunnar@biokemi.su.se.

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Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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