Studying the Proteins that Underlie Cancer

A Fulbright scientist who studies protein structures associated with the cell transformation that causes cancer has received a five-year, $661,018 grant from the National Institutes of Health to expand his research.

Paul Adams, assistant professor of chemistry and biochemistry, studies members of the Ras family of proteins. Mutants of these proteins have been found in up to 30 percent of cancer cell types, making them of interest to researchers who are trying to determine what goes wrong inside a cell, causing it to become malignant.

“We expect to provide information at the molecular level that will shed light on mechanisms that lead to abnormal cell proliferation, transformation, invasion, and metastasis,” Adams says.

Adams will use nuclear magnetic resonance and fluorescence spectroscopy to study the protein Cdc42 (Cell division cycle 42), which is involved in cell signaling pathways. But a particular construct of this protein — one in which the protein is devoid of nucleotide — can cause it to induce cell transformation, the kind of uncontrolled growth found in cancer cells. The nucleotide-free protein interacts with an oncogenic protein, which then causes cells to proliferate.

“Without the nucleotide binding site, this oncogenic protein, DBL, binds optimally to Cdc42,” Adams says. “Researchers hypothesize that flexibility in an important region of Cdc42 facilitates a strong interaction.” Adams likened the protein’s flexibility to flexible people, who can “bond” with many people, as opposed to rigid people, who bond to fewer people.

The researchers will study the structure of the nucleotide-free form of Cdc42 to determine if the conformation of the nucleotide binding site is altered relative to the regions of the protein thought to interact with the tumor causing protein.

The second part of the research will involve studying a double mutant form of Cdc42 that is thought to block cell transformation caused by a single mutation. An oncogenic mutant of Cdc42 is known to be cell transforming due to an increased rate of exchange between its active and its inactive forms. When a 13-amino acid region in Cdc42, designated the Rho insert region, is removed from an oncogenic mutant, efficient cycling between the active and inactive states occurs, but the ability of the mutant protein to transform is lost. The premise for these studies is that the structure and dynamics of this double mutant of Cdc42 will outline the conformational changes in the protein, and reveal how these changes alter the interactions with effector proteins that facilitate oncogenic events without disturbing signal transduction.

Adams will be using nuclear magnetic resonance spectroscopy in the Center for Protein Structure and Function to study the structure of these proteins and their interactions with different biomolecules that may affect the normal cell signaling functions of this Ras protein. This technique allows researchers to determine interatomic distances between atoms within a molecule by measuring the intensity of resonance signals of individual nuclei in the molecule. These distances are in turn used to determine the structures of the different proteins.

 

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