Important advance in understanding the complex interactions between proteins

Interactions between proteins are the engines that drive the lives of cells, and a better understanding of these relationships -- and the structures that enable them -- are the next great frontier in the biological sciences.

Now, a discovery by Weill Cornell Medical College researchers is changing decades-old conventional wisdom on the "coiled coil," a common protein structural motif scientists thought they knew well.

The finding, recently published in the journal Structure, marks an incremental but important advance in understanding the complex, three-dimensional interactions between these building blocks of life.

"A deeper knowledge of these types of relationships is crucial, because it gets us a tiny step closer to recreating them artificially -- using 'designer proteins' to treat and even cure disease," explains senior author Dr. Min Lu, Associate Professor of Biochemistry at Weill Medical College of Cornell University, New York City.

While the sequencing of the human genome was justly hailed as a milestone, it may prove to be just a stop on the way to a much bigger prize -- protein engineering.

"Remember, genes are simply the code that cells use to make proteins," Dr. Lu explains.

Every day, the body creates tens of thousands of different proteins that fold together in complex, three-dimensional ways to perform specific functions.

"Understanding, fixing, and even reproducing these interrelationships is really the next scientific frontier, with infinite possibilities for the health sciences and beyond. Right now, however, we know very little about the way proteins fold," he says.

One of the few types of protein-protein interactions that scientists thought they understood was the "coiled coil."

"Coiled coils occur when a very common protein structure, called an alpha helix, comes together with another alpha helix," explains lead author Dr. Yiqun Deng, a postdoctoral associate in the Department of Biochemistry at Weill Cornell. "The coil that's formed is made up of repeats of seven amino acids, so scientists call it a 'heptad repeat.'"

Each of these seven positions is named after a letter of the alphabet -- a, b, c, and s o on, up to g. For years, experts on the coiled coil asserted that two positions -- "a" and "d" -- were especially important to maintaining the structure's integrity.

But in complex experiments done in his lab, Dr. Lu's team has discovered that the seventh position, "g," is also crucial to maintaining the coiled coil interconnection.

"Even more interesting, it's not so much stabilizing the structure as it is keeping it from forming other, new conformations," he says. "It's a kind of deterrent."

That may not sound like a big difference, but the discovery marks a major shift in research into protein folding.

"Our work shows that when it comes to the coiled coil, we've all oversimplified this relationship," Dr. Deng says. "If we ever hope to recreate this structure artificially -- which we definitely want to do -- we now know that we must pay close attention not only to the 'a' and 'd' position, but to 'g' as well.'"

The finding also has implications for the burgeoning field of nanobiotechnology, where scientists hope to design incredibly small molecules that work as tiny machines.

"Before this study, we were going down the wrong track in terms of the coiled coil," Dr. Lu said. "We had a flawed understanding of how this structure was assembled."

Much more research lies ahead, he adds.

"It's an incredibly complex, challenging field, and we still don't have the full picture of even this relatively simple structure," Dr. Lu says. "But now we're one step closer."

This work was supported by grants from the National Institutes of Health and the Irma T. Hirschl Trust.

Co-authors include Dr. Jie Liu, Dr. Qi Zheng, and Dr. David Eliezer -- all of Weill Cornell Medical College; and Dr. Neville R. Kallenbach, of New York University.

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