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J. Biol. Chem., Vol. 282, Issue 15, 10972-10980, April 13, 2007

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The Selenium-rich C-terminal Domain of Mouse Selenoprotein P Is Necessary for the Supply of Selenium to Brain and Testis but Not for the Maintenance of Whole Body Selenium^*

Kristina E. Hill, Jiadong Zhou, Lori M. Austin, Amy K. Motley, Amy-Joan L. Ham^¶, Gary E. Olson^||, John F. Atkins^**1, Raymond F. Gesteland, and Raymond F. Burk²

From the Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, the ^¶Department of Biochemistry, and the ^||Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, the Eccles Institute of Human Genetics, University of Utah, Salt Lake City, Utah 84112, and the ^**Biosciences Institute, University College Cork, Cork, Ireland

Selenoprotein P (Sepp1) has two domains with respect to selenium content: the N-terminal, selenium-poor domain and the C-terminal, selenium-rich domain. To assess domain function, mice with deletion of the C-terminal domain have been produced and compared with Sepp1^–/– and Sepp1^+/+ mice. All mice studied were males fed a semipurified diet with defined selenium content. The Sepp1 protein in the plasma of mice with the C-terminal domain deleted was determined by mass spectrometry to terminate after serine 239 and thus was designated Sepp1^240–361. Plasma Sepp1 and selenium concentrations as well as glutathione peroxidase activity were determined in the three types of mice. Glutathione peroxidase and Sepp1^240–361 accounted for over 90% of the selenium in the plasma of Sepp1^240–361 mice. Calculations using results from Sepp1^+/+ mice revealed that Sepp1, with a potential for containing 10 selenocysteine residues, contained an average of 5 selenium atoms per molecule, indicating that shortened and/or selenium-depleted forms of the protein were present in these wild-type mice. Sepp1^240–361 mice had low brain and testis selenium concentrations that were similar to those in Sepp1^–/– mice but they better maintained their whole body selenium. Sepp1^240–361 mice had depressed fertility, even when they were fed a high selenium diet, and their spermatozoa were defective and morphologically indistinguishable from those of selenium-deficient mice. Neurological dysfunction and death occurred when Sepp1^240–361 mice were fed selenium-deficient diet. These phenotypes were similar to those of Sepp1^–/– mice but had later onset or were less severe. The results of this study demonstrate that the C terminus of Sepp1 is critical for the maintenance of selenium in brain and testis but not for the maintenance of whole body selenium.

Received for publication, January 16, 2007 , and in revised form, February 13, 2007.

^* This work was supported by National Institutes of Health Grants ES02497, HD44863, and ES00267. 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 Supported by an award from the Science Foundation of Ireland.

² To whom correspondence should be addressed: 1030C Medical Research Bldg. IV, Vanderbilt Medical Center, Nashville, TN 37232-0252. Tel.: 615-343-4748; Fax: 615-343-6229; E-mail: raymond.burk{at}vanderbilt.edu.

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