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Crystal structure of the human vascular adhesion protein-1: Unique structural features with functional implications

¹ Department of Biochemistry and Pharmacy, Åbo Akademi University, FIN-20520 Turku, Finland
² BioTie Therapies Corporation, Biocity, FIN-20520, Turku, Finland
³ MediCity Research Laboratories, University of Turku, and the National Public Health Institute, FIN-20520 Turku, Finland

(RECEIVED March 4, 2005; FINAL REVISION April 27, 2005; ACCEPTED May 23, 2005)

The expression of human vascular adhesion protein-1 (hVAP-1) is induced at sites of inflammation where extravasation of lymphocytes from blood to the peripheral tissue occurs. We have solved the X-ray structure of hVAP-1, a human copper amine oxidase (CAO), which is distinguished from other CAOs in being membrane-bound. The dimer structure reveals some intriguing features that may have fundamental roles in the adhesive and enzymatic functions of hVAP-1, especially regarding the role of hVAP-1 in inflammation, lymphocyte attachment, and signaling. Firstly, Leu469 at the substrate channel may play a key role in controlling the substrate entry; depending on its conformation, it either blocks or gives access to the active site. Secondly, sugar units are clearly observed at two of the six predicted N-glycosylation sites. Moreover, mutagenesis analysis showed that all of the predicted sites were glycosylated in the protein used for crystallization. Thirdly, the existence of a solvent-exposed RGD motif at the entrance to each active site in hVAP-1 suggests that it may have a functional role.

Keywords: hVAP-1; structure; amine oxidase; inflammation; glycosylation

Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.051438105.

Reprint requests to: Tiina Salminen, Department of Biochemistry and Pharmacy, Åbo Akademi University, Tykistökatu 6, FIN-20520 Turku, Finland; e-mail: tiina.salminen{at}abo.fi; fax: +358-2-2153280.

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