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J. Biol. Chem., Vol. 282, Issue 15, 11163-11171, April 13, 2007

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Specific Features of the Prion Protein Transmembrane Domain Regulate Nascent Chain Orientation^*

Carolyn M. Ott¹, Armin Akhavan², and Vishwanath R. Lingappa^¶3

From the Departments of Biochemistry and Biophysics and ^¶Physiology and Medicine, University of California, San Francisco, California 94143 and California Pacific Medical Center Research Institute, San Francisco, California 94107

The sequence of a transmembrane (TM) domain and the adjacent regions are important for recognition, orientation, and integration at the translocon during membrane protein biosynthesis. However, the sequences of individual TM domains vary considerably. Although some general effects of electrostatic and hydrophobic interactions have been observed, it is still not clear what features of diverse sequences influence TM domain orientation. Here we utilized the ability of the prion protein (PrP) to be synthesized in multiple topological forms to assay the effects of substitutions and mutations on TM domain orientation. Several of the TM domains we tested appear to contain no inherent information regulating orientation. In contrast, we found that the middle region of the PrP TM domain significantly reduces the ability of the chain to invert its orientation in the translocon. We also observed that the C-terminal region of the PrP TM domain influences orientation, and we characterized the orientation differences between two forms of a physiologically relevant polymorphism in this region. Specifically, we found that the identity of a single amino acid, that at position 129, can significantly alter PrP TM domain orientation. Because position 129 is the location of the disease-associated Met/Val polymorphism, we discuss both how this small change may affect TMD orientation and the larger biological implications of these results.

Received for publication, August 11, 2006 , and in revised form, January 22, 2007.

^* This research was supported by National Institutes of Health Grants NS37365 and AG02132 (to V. R. L.). 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.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental figure.

¹ Supported by a Howard Hughes Medical Institute predoctoral fellowship. Present address: Cell Biology and Metabolism Branch, NICHD, National Institutes of Health, Bethesda, MD 20892.

² Supported by the Heart and Stroke Foundation of Canada.

³ A founder and Chief Technology Officer of Prosetta Corp. To whom correspondence should be addressed: Dept. of Physiology, University of California, San Francisco, 513 Parnassus Ave., San Francisco, CA 94143-0444. Tel.: 415-681-0183; Fax: 415-681-2644; E-mail: vishwanath.lingappa{at}ucsf.edu.

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