Scientists find the turning point that determines protein fate

The scientists just "resurrected" the ancient ancestor of an important human protein and studied its evolutionary history which has always constantly showing mutations and analyzed a large number of alternative histories. Research shows that only two special mutations occur can ancient proteins evolve into modern glucocorticoid receptor (GR). These two permissive mutations have no effect on protein function, but they are the key base of functional mutations. The researchers screened thousands of evolutionary pathways and found that ancient GR evolved the sensitivity to cortisol in only one way. Related research papers were published in the journal Nature which also published many other studies on recombinant proteins.

Senior author of the paper, Professor Joe Thornton said, "This key protein can exist because there is a turning point in the destiny. Maybe the evolution of many body systems is dependent on the rare events in evolutionary history." He inferred the possible sequence of ancient proteins and synthesized biochemically and introduced them into a living organism to study their function.

Researchers deeply analyzed the structural effects of mutations on ancient proteins and found such rare causes. Such mutations must meet three conditions: it must stabilize specific regions in protein structure; to maintain proper energy balance among functional conformations; and it can be compatible with the original architecture and derived structure. Few mutations can meet such stringent restrictions.

The researchers found that asiding permissive mutations and only introducing functional mutations, ancient GR can't evolve into what it is today. Subsequently, they build millions of gene copies of ancient GR and introduced random mutations into each copy and simulated various possibilities in the evolution. They also produced recombinant rat proteins and designed genetically-engineered yeasts, which only grow when functional GR comes out. The researchers introduced various mutant GR into these yeasts. One any permissive mutations occur, GR function can be restored and allows yeasts to grow. Studies have shown that except two permissive mutations in reality, other mutations all can't restore GR function.

This study helps people further understand the evolution process of protein function. "Being able to directly study variable historical events is very exciting," Thornton said. "If the evolutionary history happens all over again, the results may be completely different. For cellular biochemical systems, unpredictable genetic events also shut down other possibilities when opening an evolution door."

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