Mapping the universe of a protein

SAN ANTONIO (March 18, 2011) – Andrew P. Hinck, Ph.D., spends his days methodically mapping a tiny universe inhabited by an important protein in the human body – an effort that could have an enormous impact on cancer treatment.

Dr. Hinck, professor of biochemistry at The University of Texas Health Science Center at San Antonio, studies TGF-beta (transforming growth factor beta), which controls various processes within cells. It regulates proliferation of cells – under normal circumstances, helping to suppress tumors – and also keeps the immune system in balance. He describes the latest step in that process in an article published today in The EMBO Journal, a molecular biology journal.

In the presence of cancer, the important work that the protein does for healthy cells becomes distorted and harmful. For example, due to its role in regulating the immune system, TGF-beta can suppress immune function. Cancer cells use this to their advantage, Dr. Hinck said, producing “lots and lots of TGF-beta,” which hides them from immune cells. Cancer cells also switch off TGF-beta’s tumor suppression function.

If researchers can understand exactly how TGF-beta interacts with cells, they can design cancer-fighting drugs that will stop its tumor-promoting activity while preserving its critical role in healthy cells.

Dr. Hinck is pinpointing exactly how the protein interacts with receptors on cells to do its work. The research is taking place through the Experimental and Developmental Therapeutics (EDT) program at the UT Health Science Center’s Cancer Therapy & Research Center (CTRC).

TGF-beta binds to receptors that extend through cell membranes. The part of the receptor located outside the membrane docks with TGF-beta; the portion inside, called a “kinase,” reacts to the docking by transmitting signals that spur certain actions by the cell.

When it connects to cells, TGF-beta simultaneously engages to two types of receptors. Dr. Hinck was corresponding author on a 2008 paper that described the molecular structure of TGF-beta when it is bound to those two receptors.

The next step is figuring out how the two receptor kinases – the signaling antennae – work to transmit signals inside cells. A paper that Dr. Hinck and his colleagues published in the EMBO Journal describes one step in this process. “If you can figure out how the kinases interact and work, you can make drugs that interrupt the process,” Dr. Hinck said.

In the absence of TGF-beta, the two receptors normally drift along the cell membrane and have no relationship with each other. But when TGF-beta arrives, it brings the receptors together.

One of the two receptor types is always, in effect, switched on. When that receptor binds to TGF-beta, its kinase connects to the kinase of the second receptor, activating it and triggering a cellular response.

An additional twist: TGF-beta is a special type of molecule called a “dimer,” which consists of two simpler, identical molecules bound together. Each of those simple molecules docks to two receptors – one of each type – meaning the larger TGF-beta protein complex binds to a total of four receptors.

Scientists had wondered whether the two receptor pairs worked independently of one another or if they work together toward a common goal. Dr. Hinck and his colleagues answered this longstanding question, finding that the pairs work separately from each other.

They reached this conclusion by generating an artificial form of TGF-beta that is capable of binding to only one pair of receptors – unlike natural TGF-beta, which binds to two pairs at a time. Researchers found the single pair worked nearly as well as the double pair.

Now researchers want to further unravel how the two kinases in each receptor pair interact with each other at the molecular level. The goal, Dr. Hinck said, is to create “small molecule mimics” that can bind and block activity, especially in the presence of cancer and other diseases where TGF-beta is harnessed to drive tumor growth.

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