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J. Biol. Chem., Vol. 281, Issue 14, 9423-9431, April 7, 2006

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Targeted Disruption of Tyrosylprotein Sulfotransferase-2, an Enzyme That Catalyzes Post-translational Protein Tyrosine O-Sulfation, Causes Male Infertility^*

Atefeh Borghei¹, Ying-Bin Ouyang¹², Andrew D. Westmuckett, Matthew R. Marcello, Carlisle P. Landel^¶3, Janice P. Evans, and Kevin L. Moore^||**4

From the Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, Division of Reproductive Biology, Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, Maryland 21205, ^¶The Jackson Laboratory, Bar Harbor, Maine 04609, the Departments of ^||Medicine and ^**Cell Biology, and the Oklahoma Center for Medical Glycobiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104

Tyrosine O-sulfation is a post-translational modification mediated by one of two Golgi tyrosylprotein sulfotransferases (TPST-1 and -2) expressed in all mammalian cells. Tyrosine sulfation plays an important role in the function of some known TPST substrates by enhancing protein-protein interactions. To explore the role of these enzymes in vivo and gain insight into other potential TPST substrates, TPST-2-deficient mice were generated by targeted disruption of the Tpst2 gene. Tpst2^+/- mice appear normal and, when interbred, yield litters of normal size with a Mendelian distribution of the targeted mutation. Tpst2^-/- mice have moderately delayed growth but appear healthy and attain normal body weight by 10 weeks of age. In contrast to Tpst1^-/- males that have normal fertility, Tpst2^-/- males are infertile. Tpst2^-/- sperm are normal in number, morphology, and motility in normal media and appear to capacitate and undergo acrosomal exocytosis normally. However, they are severely defective in their motility in viscous media and in their ability to fertilize zona pellucida-intact eggs. Adhesion of Tpst2^-/- sperm to the egg plasma membrane is reduced compared with wild type sperm, but sperm-egg fusion is similar or even increased. These data strongly suggest that tyrosine sulfation of unidentified substrate(s) play a crucial role in these processes and document for the first time the critical importance of post-translational tyrosine sulfation in male fertility.

Received for publication, December 27, 2005 , and in revised form, January 30, 2006.

^* This work was supported in part by National Institutes of Health Grants HL74015 (to K. L. M.), RR01262, and RR09781 (to C. P. L.) and HD037696 and HD045671 (to J. P. E.). 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 These two authors contributed equally to this work.

² Present address: Xenogen Biosciences, Cranbury, NJ 08512.

³ Present address: Dept. of Microbiology and Immunology and the Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107.

⁴ To whom correspondence should be addressed: Oklahoma Medical Research Foundation, 825 NE 13th St., Oklahoma City, OK 73104. Tel.: 405-271-7314; Fax: 405-271-7417; E-mail: kevin-moore{at}omrf.ouhsc.edu.

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