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J. Biol. Chem., Vol. 279, Issue 25, 26052-26057, June 18, 2004

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Transmembrane Domain Modulates Sorting of Membrane Proteins in Toxoplasma gondii^*

Verena Karsten¶, Ramanujan S. Hegde||, Anthony P. Sinai**, Mei Yang, and Keith A. Joiner

From the Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520 and the ^||Cell Biology and Metabolism Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892-5430

Overlapping mechanisms that function simultaneously in the intracellular sorting of mammalian membrane proteins often confound delineation of individual sorting pathways. By analyzing sorting in the evolutionarily simpler organism Toxoplasma gondii, we demonstrate a role for transmembrane domain (TMD) length in modulating the signal-dependent segregation of membrane proteins to distinct intracellular organelles. The dense granule localization of the single pass transmembrane protein GRA4 could be completely rerouted to the Golgi and cell surface simply by replacement of its TMD with that from either vesicular stomatitis virus G or the low density lipoprotein (LDL) receptor. Mutational and biochemical analyses suggested that this effect was not caused by any specific sequence motif or strength of membrane association of the GRA4 TMD. Instead, a property imparted by the vesicular stomatitis virus G or LDL receptor TMDs, both of which are longer than the GRA4 TMD, appeared to be a decisive factor. Indeed, shortening the LDL receptor TMD to a length similar to that of GRA4 resulted in dense granule localization, whereas lengthening the GRA4 TMD resulted in rerouting to the Golgi. From these data, we conclude that although the TMD may not necessarily be a sole determinant in membrane protein sorting, its properties can markedly modulate the utilization of more conventional signal-mediated sorting pathways.

Received for publication, January 15, 2004 , and in revised form, March 29, 2004.

^* 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.

Both authors contributed equally to this work.

^¶ Current address: Vion Pharmaceuticals, New Haven, CT 06511.

^** Current address: University of Kentucky College of Medicine, Dept. of Microbiology, Immunology, and Molecular Genetics, Lexington, KY 40536-0084.

To whom correspondence should be addressed: College of Medicine, University of Arizona Health Sciences Center, 1501 N. Campbell Ave., Rm. 2205, Tucson, AZ 85724. Tel.: 520-626-4555; Fax: 520-626-6252; E-mail: kjoiner{at}u.arizona.edu.

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