title: How vitronectin binds PAI-1 to modulate fibrinolysis and cell migration.
abstract: The interaction of the plasma protein vitronectin with plasminogen activator inhibitor-1 (PAI-1) is central to human health. Vitronectin binding extends the lifetime of active PAI-1, which controls hemostasis by inhibiting fibrinolysis and has also been implicated in angiogenesis. The PAI-1-vitronectin binding interaction also affects cell adhesion and motility. For these reasons, elevated PAI-1 activities are associated both with coronary thrombosis and with a poor prognosis in many cancers. Here we show the crystal structure at a resolution of 2.3 A of the complex of the somatomedin B domain of vitronectin with PAI-1. The structure of the complex explains how vitronectin binds to and stabilizes the active conformation of PAI-1. It also explains the tissue effects of PAI-1, as PAI-1 competes for and sterically blocks the interaction of vitronectin with cell surface receptors and integrins. Structural understanding of the essential biological roles of the interaction between PAI-1 and vitronectin opens the prospect of specifically designed blocking agents for the prevention of thrombosis and treatment of cancer.
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 2XY, UK.
authors.forename: Aiwu
authors.initials: A
authors.lastname: Zhou
authors.forename: James A
authors.initials: JA
authors.lastname: Huntington
authors.forename: Navraj S
authors.initials: NS
authors.lastname: Pannu
authors.forename: Robin W
authors.initials: RW
authors.lastname: Carrell
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Read
mesh_terms: D000595:Amino Acid Sequence; D002465:Cell Movement; D003460:Crystallization; D005342:Fibrinolysis; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017395:Plasminogen Activator Inhibitor 1 / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D019096:Vitronectin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D011994:Recombinant Proteins; D019096:Vitronectin