ZAG - an MHC-related protein involved in regulating lipid metabolism

ZAG - an MHC-related protein involved in regulating lipid metabolism

Zn-associated alpha(2) glycoprotein (ZAG) occurs normally in a range of biological fluids in humans. Its biological function is still mysterious but it is associated with cachexia in cancer patients. Cachexia causes the extreme loss of body fat tissue, rendering a patient much less able to survive certain treatments for cancer. So, in addition to potentially leading to an improvement in treatment through controlling cachexia, we studied ZAG to understand how it works. Our interest had been triggerd by the crystal structure of ZAG (solved by Luis Sanchez in Pamela Bjorkman's lab http://www.its.caltech.edu/~bjorker/index.html ). The protein is like class I MHC proteins, and has a groove in the same place in the structure as MHC proteins hold peptides or glycolipids for anitgen presentation to the immune system. The crystal structure revealed a small ligand in the groove, but not what the ligand could be. Click here to see a rotating model of ZAG http://www.its.caltech.edu/~bjorker/Structures/zag1.gif  .We found that the unidentified ligand is probably a polyunsaturated fatty acid, or something similar. We went on to mutate the amino acids surrounding the ligand and identified which were essential to ligand binding. Knowing what the ligand is, and how to change the protein so that it no longer binds, could be useful in developing methods to control the type of cachexia with which ZAG is involved, or provide tools for research into a better understanding of how it regulates the lipid and fat load of cells and tissues.