Patricia Clark, the Rev. John Cardinal O'Hara, C.S.C. Professor of Chemistry & Biochemistry, has received two NIH grants totaling $3.36 million for studies on protein folding. Clark, who has been a member of the faculty since 2001, won a $1.86 million competitive renewal of her previous five-year NIH grant for research on the influence of protein synthesis on folding mechanisms for newly synthesized proteins. She also won a new $1.5 million NIH grant to continue research in her laboratory first funded by an NSF CAREER Award and a National Research Development Award from the American Heart Association.
Research in Clark's laboratory is focused on understanding how proteins fold in living cells. More than 50 years ago, scientists discovered that the folding of a protein into its active, 3D structure is directed by the sequence of amino acids that make up the protein. Since then, scientists have been trying to decipher the "rules" that lead a specific amino acid sequence to produce a specific folded structure. But recent research has shown that the cellular environment can affect protein folding. Specifically, Clark's laboratory has demonstrated that the rate at which a protein is synthesized ("translated") can affect whether a protein will fold correctly, or not. Since incorrect folding leads to numerous, diverse human diseases, including Alzheimer's, Parkinson's, cystic fibrosis, Neimann-Pick and many forms of cancer, Clark has now focused her attention on understanding the precise mechanisms by which protein translation rate can affect folding for medically-relevant proteins.
Clark's new NIH grant will support research specifically aimed at understanding how the structure and folding of a particular group of proteins helps transport them to the outer surface of Gram-negative bacteria. These proteins were originally named "autotransporters" because they appear to transport themselves, without requiring assistance from other parts of the cell. Clark's lab has now shown that the structural and folding properties of these proteins are finely tuned to facilitate transport.
Autotransporter proteins occur only on bacteria responsible for such diseases as whooping cough, bacterial meningitis, cholera, and bubonic plague. Clark expects that understanding the link between autotransporter folding and transport will reveal ways to interfere with this process, and thereby treat diseases. "Our research projects always start by trying to learn more about the fundamental physical principles that underlie biology," Clark says, "but it is very gratifying to receive this new grant , as it represents the translation of our findings towards something that will directly impact human health."