Studying a cancer-causing protein in 3-D
Cancer often arises from mutations in the DNA of normal cells that make cellular processes go awry. Dr Mani Larijani, an immunology and cancer researcher and associate professor at the Memorial University of Newfoundland in St John’s, is focused on pinpointing how an enzyme called AID fits into this process.
To create an immune system capable of recognizing a diverse set of triggers, AID mutates specific genes in immune cells. These mutated genes are intended to create millions of slightly different proteins capable of detecting the vast number of infections or foreign materials one might encounter.
However, AID activity is sometimes misdirected in immune cells or mistakenly turned on in non-immune cells. This can lead to different types of cancer, including aggressive leukemias or lymphomas. AID also helps cancer cells to rapidly change and adapt, allowing them to escape treatment.
With the support of the Canadian Cancer Society, Dr Larijani has been studying the structure of AID in order to design new treatments to block its harmful effects. Building a map of the shape of AID could identify the ideal spots to target with anticancer therapeutics.
Despite intense efforts by many researchers since the discovery of AID, the structure of this protein had been elusive. Dr Larijani and his team approached this problem using a new cutting-edge method. They combined computer simulations and biochemical experiments to discover the 3-D structure of AID on its own and while it interacts with DNA. They discovered that AID has a built-in safety switch – most of the time, it takes a shape that cannot cause DNA mutations.
Dr Larijani explains, “Knowing the functional structure of AID will allow us and others to design drugs to block its activity in cancer. We have also pioneered a new methodology that provides a great deal of information not just on the structure of molecules, but on how structure regulates function.”