The study resurrecting protein ancestors yields; evolutionary insights into their role in human cells. Resurrecting the ancestors of key proteins yields evolutionary insights into their role in human cells and in most cancers; study revolving around the function of extracellular signal regulating kinase (ERK); a protein that determines whether human cells divide and multiply as part of growth.
Specifically, the research team used computer analyses to determine the DNA sequences, and related protein structures, for ancient ERK relatives. By studying them, the researchers identified two key changes that likely brought ERK under more careful control across evolution.
This becomes important, the researchers say, because a similar process occurs as genetic mistakes convert normal cells into cancer. Modern day ERK is part of the most important signaling pathway in human cancers; along with the other protein switches that get stuck in the on position to cause abnormal growth. Like all proteins, versions of ERK are assembling from the combinations of molecular building blocks called amino acids.
Role in human cells
However, by using the standard biochemical techniques to produce proteins with the predicted sequences, and showing that the predicting common ancestor of ERK1/2 could not autophosphorylate efficiently, whereas other ancestral MAP kinases could. Two mutations were found when the sequence of the ERK1/2 common ancestor was compared to the sequences of the other ancestral MAP kinases.
The growing variety of amino acid structures across the animal kingdom now cataloged in databases has made possible a new kind of analysis, say the authors. Researchers can make educated guesses about the amino acids occupying each position in the structures of their common ancestors. One was an amino acid substitution near the spine connecting different regions of the protein; the other was an amino acid deletion that shortened a flexible loop near the catalytic cleft in the kinases.
Screening drug candidates
The research team plans to resurrect a complete set of inferred ancestors for all proteins in ERK’s class (kinases), and to screen drug candidates against them, says Holt. Their plan is basing on the hypothesis that some mutations cause cancer because they return kinases to more ancient stating that are not properly regulating.
The two mutations reported in the latest work have intriguing implications for kinases in general. But alterations to the flexible loop have been observing in cancer associating variants of several distantly related kinases; and mutations at the spine proximal position are associating with excessive activation and drug resistance in a variety of kinases.