Yale Researchers Map Protein Binding that is Critical to Life

A Yale School of Medicine laboratory has succeeded in mapping and describing an interaction important for cell adhesion, a process critical to life, and, 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,” said 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 said 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 said.

His lab set out to examine the interaction between integrins and filamin. Filamin 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 and also 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 said. His group, working in collaboration with researchers in Finland and the United Kingdom and using X-ray crystallography and nuclear magnetic resonance spectroscopy, also provided 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,” he said. “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, Finland; Yatish Lad and Massimiliano Baldassarre, Yale; Pengju Jiang, Camilla Oxley, Kate Wegener, Iain Campbell from Oxford.

Molecular Cell, Vol 21,: 337-347 (February 2, 2006)

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