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J. Biol. Chem., Vol. 281, Issue 21, 14644-14653, May 26, 2006

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Distinct Glycan Structures of Uroplakins Ia and Ib

STRUCTURAL BASIS FOR THE SELECTIVE BINDING OF FimH ADHESIN TO UROPLAKIN Ia^*

Bo Xie¹, Ge Zhou¹, Shiu-Yung Chan, Ellen Shapiro^¶, Xiang-Peng Kong^||, Xue-Ru Wu^¶**, Tung-Tien Sun^¶2, and Catherine E. Costello²

From the Mass Spectrometry Resource, Boston University School of Medicine, Boston, Massachusetts 02118 and Departments of Dermatology, ^¶Urology, ^||Biochemistry, ^**Microbiology, and Pharmacology, New York University School of Medicine, New York, New York 10016

Although it has been shown that mouse uroplakin (UP) Ia, a major glycoprotein of urothelial apical surface, can serve as the receptor for the FimH lectin adhesin of type 1-fimbriated Escherichia coli, the organism that causes a great majority of urinary tract infections, the glycan structure of this native receptor was unknown. Using a sensitive approach that combines in-gel glycosidase and protease digestions, permethylation of released glycans, and mass spectrometry, we have elucidated for the first time the native glycoform structures of the mouse UPIa receptor and those of its non-binding homolog, UPIb, and have determined the glycosylation site occupancy. UPIa presents a high level of terminally exposed mannose residues (located on Man₆GlcNAc₂ to Man₉GlcNAc₂) that are capable of specifically interacting with FimH. We have shown that this property is conserved not only in the mouse uroplakins but also in cattle and, even more importantly, in human UPIa, thus establishing the concept that UPIa is a major urothelial receptor in humans and other mammals for the mannose-specific FimH variant. In contrast, our results indicate that most terminally exposed glycans of mouse UPIb are non-mannose residues, thus explaining the failure of FimH to bind to this UPIb. In cattle, on the other hand, complex carbohydrates constituted only about 20% of the UPIb N-linked glycans. Human UPIa contained exclusively high mannose glycans, and human UPIb contained only complex glycans. The drastically different carbohydrate processing of the UPIa and UPIb proteins, two closely related members of the tetraspanin family, may reflect differences in their folding and masking due to their interactions with their associated proteins, UPII and UPIIIa, respectively. Results from this study shed light on the molecular pathogenesis of urinary tract infections and may aid in the design of glyco-mimetic inhibitors for preventing and treating this disease.

Received for publication, January 27, 2006 , and in revised form, March 21, 2006.

^* This work was supported by National Institutes of Health Grants P41 RR10888 and S10 RR15942 (to C. E. C.), R01 DK39753 (to T.-T. S.), and P01 DK52206 (to X.-P. K., X.-R. W. and T.-T. S.). 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 Figs. 1–6.

¹ These authors have made equal contributions.

² To whom reprint requests and correspondence should be addressed: Mass Spectrometry Resource, Departments of Biochemistry and Biophysics, Boston University School of Medicine, 670 Albany St., Rm. 511, Boston, MA 02118. Tel.: 617-638-6490; Fax: 617-638-6491; E-mail: cecmsms{at}bu.edu.

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