Assistant Professor Damien Mathew PhD

Radiation Oncology
Medical School
Twin Cities
Project Title: 
Cancer Metabolism and Radiosensitivity

This group is currently studying a protein phosphatase, PP2A. This enzyme is generally believed to be a tumor suppressor, however recent studies have shown that inhibition of PP2A by certain molecules leads to improved outcomes for cancerous tumors under treatment in mice. 

Part of the difficulty in studying PP2A is its complex structural nature; PP2A, in its functional form, is a holoenzyme consisting of three separate chains of proteins. Of particular interest are the four families of the "B" chain of PP2A. These families are the B family (also called PR55alpha), the B' family (sometimes called PR61 gamma 1), the B'' family (called PR72" and finally the B''' family (referred to as the "Striatins").

This group's goal is to utilize molecular dynamics simulations to aid in determining a network of atomic connections that hold these chains together in a functional holoenzyme structure. A similar type of analysis was performed to determine amino-acyl tRNA synthetase charging by the Luthey-Schulten group at the University of Illinois. The dynamical network model uses the likelyhood of positions of atoms of interest over time throughout the trajectory of a modecular dynamics simulation. Should an atom stay within a sphere of a specified distance for longer than a specified fraction of total simulated time the atoms are said to be in a community. Each community is linked by "critical nodes." So far, these researchers have finished the dynamical network analysis for one type of PP2A holoenzyme and the critical nodes seem to agree with cancerous hotspots. Further studies with additional proteins will be needed to validate that this type of analysis can find cancerous hotspots. In addition, the network model also helps glean insight into why these particular mutations lead to cancer. For the completed network model, the critical nodes are part of the "hinge" of chain A onto the catalytic chain C. The mutation could likely lead to dissociation of weakening of chain A leading to a loss of function.

Project Investigators

Assistant Professor Damien Mathew PhD
 
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