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J. Biol. Chem., Vol. 282, Issue 45, 32912-32923, November 9, 2007

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Oligomerization and Transglutaminase Cross-linking of the Cystatin CRES in the Mouse Epididymal Lumen

POTENTIAL MECHANISM OF EXTRACELLULAR QUALITY CONTROL^*

Hans H. von Horsten¹, Seethal S. Johnson, Susan K. SanFrancisco, Mary Catherine Hastert^¶, Sandra M. Whelly, and Gail A. Cornwall²

From the Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, the Center for Biotechnology and Genomics, and the ^¶Imaging Center, Department of Biological Sciences, Texas Tech University, Lubbock, Texas 79430

CRES (cystatin-related epididymal spermatogenic), a member of the cystatin superfamily of cysteine protease inhibitors, is expressed in the epididymis and spermatozoa, suggesting specialized roles in reproduction. Several cystatin family members oligomerize, including cystatin C that forms amyloid deposits associated with cerebral amyloid angiopathy. Our studies demonstrate that CRES also forms oligomers. Size exclusion chromatography revealed the presence of multiple forms of CRES in the epididymal luminal fluid, including SDS-sensitive and SDS-resistant high molecular mass complexes. In vitro experiments demonstrated that CRES is a substrate for transglutaminase and that an endogenous transglutaminase activity in the epididymal lumen catalyzed the formation of SDS-resistant CRES complexes. The use of a conformation-dependent antibody that recognizes only the oligomeric precursors to amyloid, negative stain electron microscopy, and Congo Red staining showed that CRES adopted similar oligomeric and fibrillar structures during its aggregation as other amyloidogenic proteins, suggesting that CRES has the potential to form amyloid in the epididymal lumen. The addition of transglutaminase, however, prevented the formation of CRES oligomers recognized by the conformation antibody by cross-linking CRES into an amorphous structure. We propose that transglutaminase activity in the epididymal lumen may function as a mechanism of extracellular quality control by diverting proteins such as CRES from the amyloidogenic pathway.

Received for publication, May 14, 2007 , and in revised form, August 29, 2007.

^* This work was supported by National Institutes of Health Grants HD33903 and HD44669 (to G. A. C.) and by a Howard Hughes Medical Institute grant through the Undergraduate Science Education Program to Texas Tech University. 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 supplemental Fig. 1.

¹ Present address: Dept. of Molecular Biology and Virology, ProBioGen AG, Goethestr. 54, 13086 Berlin, Germany.

² To whom correspondence should be addressed: Dept. of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, 3601 4th St., Lubbock, TX 79430. Tel.: 806-743-2687; Fax: 806-743-2990; E-mail: gail.cornwall{at}ttuhsc.edu.

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