Everything a cell does, from dividing in two to migrating to a different part of the body, is controlled by enzymes that chemically modify other proteins in the cell.
Researchers at Princeton University have devised a new mathematical technique to describe the behavior of many cellular enzymes. The approach, will help researchers determine how genetic mutations change the behaviour of these enzymes to cause a range of human diseases, which also includes cancer.
Enzymes called kinases can add phosphate molecules to multiple sites on other proteins altering their activity within the cell. Studying these “multisite phosphorylation reactions” is complicated because the phosphate groups can be added rapidly and in different orders, which may affect how the modified proteins behave within the cell.
This makes it difficult to understand exactly what goes wrong when a kinase is mutated.
A team of Princeton researchers led by Martin Wühr, an assistant professor of molecular biology, and Stanislav Shvartsman, a professor of chemical and biological engineering at Princeton and an Investigator at the Flatiron Institute, developed a mathematical model of how a kinase called MEK adds two phosphate molecules to a kinase called ERK.
This double phosphorylation activates ERK so that it can drive numerous cellular processes, including cell growth and division. Mutations in MEK and ERK can cause of several diseases, including cancer.
“There are many mutations in MEK that affect the overall levels of dually phosphorylated ERK,” Wühr said. “But the effects of these mutations on the mechanism of ERK activation remain unknown.”
