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

• Published in: Protein science 2005-08, Vol.14 (8), p.1964-1974
• Main Authors: Airenne, Tomi T., Nymalm, Yvonne, Kidron, Heidi, Smith, David J., Pihlavisto, Marjo, Salmi, Marko, Jalkanen, Sirpa, Johnson, Mark S., Salminen, Tiina A.
• Format: Article
• Language: English
• Subjects: amine oxidase; Amine Oxidase (Copper-Containing) - chemistry; Amine Oxidase (Copper-Containing) - metabolism; Amino Acid Sequence; Binding Sites; Cell Adhesion Molecules - chemistry; Cell Adhesion Molecules - metabolism; Crystallography, X-Ray; Dimerization; Glycosylation; Humans; hVAP‐1; inflammation; Models, Molecular; Molecular Sequence Data; Protein Structure, Tertiary; structure
• ISSN: 0961-8368; 1469-896X
• DOI: 10.1110/ps.051438105

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.