binding that is critical to life
A School of Medicine laboratory has succeeded in mapping and describing an interaction important for cell adhesion, a process that is critical to life and that, when it goes awry, can lead to diseases such as cancer.
Adhesion of a cell to neighboring cells or proteins transmits information into the cell that determines whether it should grow, divide, develop or move. Integrins are a family of adhesion proteins that are central to this communication and are present on almost every human cell.
"Mutations in integrins lead to bleeding disorders, defective immune responses and cancer," explains David Calderwood, assistant professor in the Department of Pharmacology and senior author of the study in Molecular Cell. "Integrins regulate inflammation, vascular disease and clot formation. On cancer cells, they can promote tumor metastasis."
He says drugs that target integrins are used to control thrombosis and are in trials for the treatment of heart disease, stroke, inflammation, multiple sclerosis and cancer. "However, a complete understanding of how integrins work is still lacking," Calderwood says.
His lab set out to examine the interaction between integrins and filamin. The latter functions as a larger molecule composed of two filamin molecules joined at one end to form a flexibile V-shaped structure. Mutations in the human filamin genes are linked to neurological and skeletal defects as well as vascular problems.
"Our lab has succeeded in mapping the region, or domain, within filamin that binds to integrins and has shown that removing this domain drastically reduces the ability of filamin to bind integrins," Calderwood says. His group, working in collaboration with researchers in Finland and the United Kingdom, also used X-ray crystallography and nuclear magnetic resonance spectroscopy to provide the first detailed molecular structure of the short intracellular integrin tail bound to filamin.
"We have identified key points of interaction and show that this mode of interaction is common for filamin binding to many of its other binding partners," Calderwood says. "Our structure also revealed two important mechanisms by which the cell can regulate the filamin-integrin interaction. This could be important for controlling integrin function and may provide a point for therapeutic intervention."
Co-authors include Tiila Kiema and Jari Ylanne from Finland; Yatish Lad and Massimiliano Baldassarre from Yale; and Pengju Jiang, Camilla Oxley, Kate Wegener and Iain Campbell from Oxford.
--By Jacqueline Weaver
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