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The researchers' model revealed how fast each phosphate group is added and how often both phosphates are added by the same enzyme. Most of the time, a single MEK enzyme binds to ERK and adds one phosphate molecule before it detaches and allows a second MEK enzyme to bind and add the second phosphate.
The researchers then used their model to analyze a mutant version of MEK that is found in human cancers. This mutant MEK was twice as fast at adding the first phosphate to ERK, and was much more likely to remain attached and add the second phosphate group itself. Together, this enhances ERK activation and accelerates cancer cell growth.
The researchers then analyzed two other MEK mutations that cause a variety of developmental abnormalities, including congenital heart defects and stunted growth. These mutations did not affect MEK's ability to add phosphate molecules to ERK. Instead, they enhance the activation of MEK by another kinase, called Raf, which adds two phosphate molecules onto MEK.
"Our analysis therefore reveals which of the multiple steps in this cascade of multisite phosphorylation are affected by each mutation," Shvartsman said. "We expect that our mathematical models will allow a deeper, more quantitative understanding of cell regulation systems, including their responses to mutations of constituent proteins."
Uncovering exactly how mutations alter enzyme function can help researchers develop new therapeutic strategies that restore their function back to normal.
"Our approach is not limited to kinases and is applicable to a broad class of biochemical mechanisms where one enzyme modifies multiple sites on its substrate," Wühr said. Source:
Princeton University Journal reference:
Yeung, E., et al. (2020) Inference of Multisite Phosphorylation Rate Constants and Their Modulation by Pathogenic Mutations. Current Biology . doi.org/10.1016/j.cub.2019.12.052 .
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