Structure of human semicarbazide-sensitive amine oxidase/vascular adhesion protein-1.
Semicarbazide-sensitive amine oxidase (SSAO) belongs to a ubiquitous family of copper-containing amine oxidases (CuAOs). SSAO is also known as vascular adhesion protein-1 (VAP-1) and has been identified as one of the adhesion molecules involved in the leukocyte-extravasation process. The structure of a truncated soluble form of human SSAO has been solved and refined to 2.5 A. As expected, SSAO is a homodimer with a fold typical of the CuAO family. The topaquinone (TPQ) cofactor and a copper ion characteristic of CuAOs are present in the active site, with the TPQ in the active ;off-copper' conformation. The structure reveals that a leucine residue (Leu469) located adjacent to the active site could function as a gate controlling its accessibility. An RGD motif is displayed on the surface, where it could be involved in integrin binding and possibly play a role in the shedding of SSAO from the membrane. Carbohydrate moieties are observed at five of six potential N-glycosylation sites. Carbohydrates attached to Asn232 flank the active-site entrance and might influence substrate specificity. The structure of an adduct of SSAO and the irreversible inhibitor 2-hydrazinopyridine has been solved and refined to 2.9 A resolution. Together, these structures will aid efforts to identify natural substrates, provide valuable information for the design of specific inhibitors and direct further studies.
Jakobsson
Emma
E
Department of Cell and Molecular Biology, Uppsala University, Biomedical Centre, Box 596, SE-751 24 Uppsala, Sweden.
Nilsson
Joakim
J
Ogg
Derek
D
Kleywegt
Gerard J
GJ
D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors / Q000737:chemistry*; D020816:Amino Acid Motifs; D001665:Binding Sites; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000737:chemistry*; D002460:Cell Line; D003300:Copper / Q000737:chemistry; D018360:Crystallography, X-Ray; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D011728:Pyridones / Q000737:chemistry* / Q000494:pharmacology
D015815:Cell Adhesion Molecules; D011728:Pyridones; C062607:2-hydrazinopyridine; D004295:Dihydroxyphenylalanine; C067626:6-hydroxydopa quinone; D003300:Copper; C076668:AOC3 protein, human; D006631:Amine Oxidase (Copper-Containing)