New study suggests 2 key protein-folding domains evolved separately

A detailed analysis of the way that proteins become bound to nucleotides, the structural units of DNA and RNA, gives insight into how key enzymes that control metabolism in all living organisms may have evolved.

The research, which focuses on the protein-folding domain known as HUP, is based on study of extensive databases of protein-folding domains found in both archaea and bacteria. 

This collaborative work, by biochemists from the University of Zagreb and the Weizmann Institute of Science in Israel, was published online in the journal Critical Reviews in Biochemistry and Molecular Biology on Aug. 12. 

Proteins are large molecules containing one or more chains of amino acids combined into a complex shape. The chains are produced by a sort of chemical machine within each cell known as a ribosome. The ribosome receives a blueprint from the cell’s genome telling it which sequence of the 22 possible amino acids to weave into the chain. 

As they first are produced in the ribosome, the proteins are simple chains of molecules, known as polypeptides. Then, by action of chemical bonds, they first combine into linkages, and then take on complex three-dimensional shapes in a process called “folding.” The folded form is the chemically and thermodynamically favored shape of the protein, and determines to what specific molecules it will bind. 

The first knowledge of protein shape, now known as the secondary structure, was discovered by Linus Pauling and collaborators in the 1940s and 1950s. These were known as the α- (alpha) helix and the β- (beta) sheet. Pauling’s α-helix was the inspiration for the DNA double helix model later deduced by Watson, Crick and Franklin. 

Modern protein studies rely on the results of X-Ray crystallography, cyrogenic electron microscopy and computational technologies. Together these have allowed scientists being characterize the tertiary structure or “folding” of countless proteins.. 

The Rossman fold and the HUP domain

The first known system of protein folding was named after Michael Rossman, who noticed a structural motif in the enzyme lactate dehydrogenase in 1970, and later saw it repeated in nucleotide-binding proteins. After 1974 this structure was found to occur frequently and came to be known as the Rossman fold. 

In 2002, Aravind L. Iyer and collaborators at the National Center for Biotechnology Information in Bethesda, Maryland, described a new system of protein folds that they called the HUP domain. 

In its architectural structure, the HUP domain is identical to the Rossman fold, and is often referred to as Rossman-like or Rossmanoid. And like the Rossman and several other folding domains, the HUP domain is involved in binding proteins to nucleotides and thus plays a role in key life processes including providing chemical energy to the cell, cell division and signaling, and preservation of the genome. 

In its architectural structure, the HUP domain is identical to the Rossman fold, and is often referred to as Rossman-like or Rossmanoid. And like the Rossman and several other folding domains, the HUP domain is involved in binding nucleotide-like molecules. Thus it plays a role in key life processes including formation of tRNA, biosynthesis of cofactors (vitamin b2, vitamin b3, and CoA), guanosine, and the amino acid asparagine.

But historically the HUP domain seems to have an independent origin from the Rossman fold. The finding that led to this conclusion is that the Rossman and HUP domain differ in the method of ribose binding. Ribose is a simple sugar produced in the body and a key component of the ribonucleotides from which RNA is built. 

This distinction leads the authors to conclude that the two domains actually evolved at different points in the evolution of these key biochemical mechanisms so essential to life. 

The study concludes, “Overall, in agreement with the assertion of multiple independent emergences of Rossmann-like domains, we surmise that the HUP and Rossmann emerged independently of one another (or diverged from a short ancestral peptide to give two separate αβα fragments).” 

The study is co-authored by Ita Gruic-Sovulj of the University of Zagreb (Croatia) and Liam Longo, Jagoda Jablonska, and DanTawfik of the Department of Biomolecular Sciences, Weizmann Institute of Science (Israel). Longo is also affiliated with the Earth-Life Science Institute, Tokyo Institute of Technology (Japan).