Research Shows How Complex Enzyme Relevant to Cancer Forms and Works
UW Carbone Cancer Center - For Researchers
Madison, Wisconsin - Researchers at the University of Wisconsin-Madison have discovered a molecular mechanism that controls essential steps in the way that PP2A, a complex enzyme frequently associated with many types of cancer, forms and works.
Led by Dr. Yongna Xing, assistant professor of oncology at the School of Medicine and Public Health, the researchers determined the atomic structure of PP2A in a complex with LCMT-1, an enzyme that plays an essential role in the survival of all cells.
"The structure revealed important mechanisms by which LCMT-1 precisely controls key steps in PP2A formation and function," says Xing, based at the McArdle Laboratory for Cancer Research and a member of the UW Carbone Cancer Center.
Understanding how the two enzymes work together may point to future ways to treat cancer, she says.
"Modulating PP2A activity and LCMT-1 function provides a potential strategy for controlling cancer cell cycle and survival," she says.
The study appears in the Feb. 3 issue of Molecular Cell.
Xing has studied many aspects of PP2A, a highly dynamic, complex enzyme involved in numerous important cellular functions, not just those related to cancer. She uses a multidisciplinary approach, exploring the structural biology, biochemistry and proteomics of the enzyme. Recently she turned her attention to the structure underlying the mechanism that stimulates the phosphatase activity of the enzyme.
"The proper formation of PP2A is critical for cell function," says Xing. "The malfunction of PP2A is closely linked to diverse human diseases, including cancer and Alzheimer's disease."
Xing's team determined the crystal structure of LCMT-1 bound to PP2A by destabilizing the dynamic enzyme using a novel chemical approach. It was the first time anyone had been able to crystallize the complex. The structure showed how LCMT-1 recognizes and modifies the active form of the core PP2A complex, driving it to assemble into a complete enzyme with three main subunits.
"This conversion guards the cell from unchecked activity while at the same time assuring that the enzyme formed resides in an active state," she says. "In this respect, LCMT-1 can be seen as a guardian of substrate-specific activity of PP2A, which is critical for cellular function."
The paper represents a breakthrough in Xing's continuum of research aimed at understanding the tight control of PP2A biogenesis.
Date Published: 02/04/2011