Scientists map protein

The secret to one of the cell’s most basic functions was recently crystallized in a lab at the Yale School of Medicine.

A Yale research team headed by Dr. David Calderwood — professor in the Department of Pharmacology and the interdepartmental program in vascular biology and transplantation at the School of Medicine — recently published their findings on the crystal structure of integrin, a vital cellular protein. In conjunction with a Finnish team and an Oxford University lab, Calderwood’s study produced the world’s first map of the crystal structure of integrin and an associated protein.

Mapping integrin will enable scientists to better understand many vital bodily processes, such as blood clotting, the immune system and the spread of tumors, Calderwood said.

“Integrins have long been pharmaceutically interesting because so many vital bodily processes are dependent on the activity of integrins,” he said. “Since they bind to extracellular molecules, they serve as signaling proteins that communicate important biological signals to tell the cell how to act.”

An example of this process is the clotting of blood, since platelet integrins are responsible for knowing when to coagulate blood.

In the paper, which was published in the Feb. 3 issue of the journal Molecular Cell, the team released its results concerning the interaction between integrin and filamin, an associated protein found inside the cell. Five years ago, the team showed that filamin was responsible for binding to the inside half of the integrin molecule to regulate cell movement.

How well filamin was controlled by the cell correlates with that cell’s motility. The study also figured out which part of filamin was responsible for binding to integrin, said Massimiliano Baldassarre, a postdoctoral fellow working in Calderwood’s lab.

The experiment had several components to it, ranging from making the filamin to biochemically analyzing pieces of the molecule to determine which are “biologically active,” able to bind to the integrin and regulate bodily processes, said Yatish Lad, another postdoctoral fellow working with Calderwood.

Some of the functions of filamin are also vital for brain function, Calderwood said. When filamin fails, diseases such as periventricular heterotopia — a heritable human disease known to cause epilepsy — can result. This is due to the failure of brain cells to migrate within the brain, a result of reduced cell motility. It almost exclusively strikes women, also causing a high number of miscarriages, he said.

Calderwood said literature indicates that integrins are necessary for organisms’ survival, and the same goes for filamin. But he said he remains unsure whether this is because the two key proteins work together.

“They have other functions, too,” Calderwood said. “We can’t yet say it’s just the binding of the two that makes these proteins so vital to life.”

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