How vitronectin binds PAI-1 to modulate fibrinolysis and cell migration

A Zhou, JA Huntington, NS Pannu, RW Carrell… - Nature Structural & …, 2003 - nature.com
A Zhou, JA Huntington, NS Pannu, RW Carrell, RJ Read
Nature Structural & Molecular Biology, 2003nature.com
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 Å …
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 Å 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.
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