“Protein folding” is the method by which proteins physically transform from long amino acid chains into functional, three-dimensional structures. Emerging research suggests that protein folding might also be the key to understanding the development of life on earth.
Modern medicine’s quest to better understand and predict protein folding patterns also has major implications in the modern world, particularly in diagnosing and treating medical conditions. Misfolded proteins in certain parts of the body can cause or exacerbate disease.
Reconstructing Ancient Thioredoxin
A team of Spanish and American scientists conducted a study analyzing the gene sequences of a protein called thioredoxin — a substance with an extremely long and consequential ancestry.
Thioredoxin is an enzyme known for its metabolic role in breaking down sulfuric bonds. Thioredoxin can be found in bacteria, animals, and even human beings. In fact, nearly all life on earth contains thioredoxin.
Using computer analysis, the researchers determined how thioredoxin’s genetic sequences developed over time. They then used this data to reverse engineer a version of thioredoxin that could be studied in its evolutionary context. That context was literally primordial, as it turns out — the oldest DNA sequence they identified would have been present on earth as long as four billion years ago when life as we understand it hardly existed at all.
Bacteria were applied to the ancient gene sequence to yield a chemically active protein which could then be studied and measured like any other protein. Of particular interest to researchers was the molecular structure, the result of some of the earliest protein folding ever to occur on earth.
Eric Gaucher, a Georgia Tech scientist involved in the gene reconstruction, explained the significance of observing this ancient protein folding: “Our approach created biochemically active proteins that fold up into three-dimensional structures that look like modern protein structures.” In other words, any error in the reconstructed gene sequence would have resulted in useless, non-viable material. Instead, the gene reconstruction was successful, the protein behaved as expected, and the researchers were essentially able to observe the earliest stages of evolutionary life in the lab.
Previous research into thioredoxin has shown that it is extremely durable and resilient. The protein can survive high acidity and extreme temperatures.
Peptides and Ancient Protein Folding
Another recent study suggests that simple protein chains called peptides evolved before DNA or RNA. The research challenges prevailing theories about how life on earth originated. It was previously accepted that RNA evolved from the so-called primordial stew, then formed peptides out of amino acids. But that model left a major question: how did the RNA itself develop?
Researchers discovered similarities in the physical structures of amino acids and RNA molecule nucleotides, which suggested that nucleotides and amino acid chains were interacting billions of years ago. They believe this is how RNA was first formed and eventually became our first single-celled ancestor.
Tests were conducted at temperatures that would have been expected 3.6 billion years ago, and even in those extreme conditions, these interactions between nucleotides and amino acids were proven possible.
Charles Carter, a University of North Carolina biochemist who was a project lead, stated in a press release that the work “shows that the close linkage between […] amino acids, the genetic code, and protein folding was […] the key factor in the evolution from building blocks to organisms.”
What It Means
John Buzzo, a senior research associate in the field of therapeutics, explains, “once a protein crashes, it’s almost impossible to refold it in the lab.” Therefore, the best hope for combating the misfolded proteins that cause disease lies in understanding and predicting the ways protein folds in the first place. Looking at protein folding throughout the entire sequence of evolution, from ancient primordial ooze to modern-day organisms, provides researchers with an invaluable data set.
As scientists continue to pursue a better understanding of protein folding and its role in the development of life, we’ll be able to better predict how, why, and when proteins fold. This knowledge could help us understand, prevent and treat various diseases.
Personal interview – Buzzo, John – Senior Research Associate, Entrada Therapeutics, Boston, MA