Do cleaved genes code for cleaved proteins?

A new study led by Peter Wolynes of Rice University provides new insights into the evolution of folding proteins. The research was published in Proceedings of the National Academy of Sciences.

Researchers at Rice and the University of Buenos Aires used energy landscape theory to distinguish between folding and unfolding parts of protein sequences. Their study sheds light on the ongoing debate over whether pieces of DNA that encode only part of a protein during their origin can fold on their own.

The researchers focused on the broad relationship between exons in protein structures and the evolution of protein folding. They emphasized the importance of exons, the parts of the gene that code for proteins, and introns, the silent regions discarded during the translation of genes into proteins.

“Using the genome-wide exon-intron organization and protein sequence data now available, we explored exon boundary conservation and assessed its behavior using theoretical energy landscape measurements,” said Wolynes, Professor of Science of the DR Bullard-Welch Foundation, Professor of Chemistry, Biosciences. , physics and astronomy and co-director of the Center for Theoretical Biological Physics (CTBP).

When fragmented genes were discovered in the 1970s, it was immediately proposed that by breaking the sequence, this structure helped build folding proteins. When researchers looked at this back in the 1990s, the existing data was inconclusive, Wolynes said.

The team has now evaluated exons as potential protein folding modules in 38 abundant and conserved protein families. Over generations, exons can be randomly shuffled throughout the genome, leading to significant changes in genes and the creation of new proteins. The findings showed deviations in the exon size distribution from exponential decay, suggesting that there was evolutionary selection.

“Protein folding and evolution are closely related phenomena,” said Ezequiel Galpern, a postdoctoral researcher at the University of Buenos Aires.

Natural proteins are linear chains of amino acids that usually fold into compact three-dimensional structures to perform biological functions. The specific amino acid sequence dictates the final 3D structure. Therefore, the idea that exons translate into regions of independently folded proteins, or foldons, is very attractive.

Using computational methods, the researchers measured the likelihood that the chain of amino acids encoded by an exon would fold into a stable 3D structure, similar to the complete protein. Their results showed that while not all exons led to folding modules, the most conserved exons, consistently found in different organisms, corresponded to the best folds.

The study found a correlation between protein folding and evolution in several families of globular proteins. Protein folding involves chains of amino acids folding in space to perform biological functions within appropriate timescales. This correlation is a fundamental concept in protein science, evaluated using genomic data and energy functions.

Interestingly, the overall trend was not across all protein families, suggesting that other biological factors may influence protein folding and evolution. The researchers’ work paves the way for future studies to understand these additional factors and their impact on evolutionary biology.

The research team includes Carlos Bueno, a postdoctoral researcher at CTPB; Hana Jaafari, an applied physics graduate student at Rice; and Diego U. Ferreiro, professor at the University of Buenos Aires.

This study was supported by the Consejo Nacional de Investigaciones Científicas y Técnicas; Bullard-Welch Chair at Rice; University of Buenos Aires; NASA Astrobiology Institute; and CTPB.