Biologists Find Structure Essential for Life
Without this ancient three-dimensional fold of protein material, DNA could not organize into chromosomes, and life as we know it would not exist. But the discovery has even broader implications; the architecture of this structure is the common element in many critical proteins, enabling the assembly, and, ultimately, the functioning of various proteins crucial for life.
Scientists call the structure the "histone fold," a specific three-dimensional arrangement of 65 amino acids. Amino acids are the building blocks of all proteins. In nature, there are many types of histones, and when they are compared to each other they appear diverse. As the Hopkins scientists found, however, each histone contains the histone fold, but its location varies from histone to histone. When the histones are lined up by their histone-fold regions, they appear strikingly similar.
The findings are being reported in the Nov. 21 issue of Proceedings of the National Academy of Sciences. The scientific paper is written by Gina Arents, a research associate in the Johns Hopkins Biology Department, and Evangelos Moudrianakis, a Hopkins biology professor.
The scientists discovered another important characteristic of the histone fold: When its two halves are analyzed separately, one appears to be a duplicate of the other, and, the researchers suggest that the present-day histone fold may be produced by a gene that has been duplicated from a primordial gene half its size.
That means scientists now can study the biological features of an ancient element of genetic structure presumably present since the emergence of life. In their upcoming paper, the researchers describe the structural characteristics of the histone fold and analyze its possible evolutionary patterns. "It is impressive that this protein folding motif has remained essentially unchanged from the most primitive forms of life to humans," said Moudrianakis. It is found in all cellular organisms, from the simplest bacteria, to fungi and the higher plants and animals.
The Hopkins scientists compared a large number of proteins, which, based on their amino acid sequences, appear unrelated. But, by using the histone fold as a new "ruler," the scientists found that the proteins are, in fact, related, and are members of a distinct protein "superfamily." The members of the family have diverse biological functions but appear to have evolved from a common and simple protein ancestor, the histone fold.
These findings allow scientists for the first time to compare possible functional analogies among proteins previously considered unrelated, leading to a better understanding of the mechanisms involved in genetic regulation, such as gene replication and gene expression.
The Johns Hopkins scientists in 1991 discovered the histone fold inside a bundle of proteins, called histones, which form spools around which DNA winds itself to make chromosomes. Without the spools, DNA could not fit inside a cell's nucleus. The DNA from one human cell, if stretched straight, would be about 7 feet long. In life, however, it is bound tight and "compacted" enough to fit inside the nucleus of each of the body's trillions of cells.
Each histone spool is made up of eight protein chains, organized in what is called a core histone octamer. Four types of histone molecules make up the spools, and each type contains the histone fold. The histone octamer is arranged in three sections, held together by weak molecular bonds that relax when it is time for a portion of the DNA to stretch out so that a particular segment of genetic code can be expressed.
An earlier, related study was initiated by the Johns Hopkins scientists, along with former graduate student Andy Baxevanis, who is now at the National Institutes of Health. Those earlier findings, released in a paper published in July 1995 in the journal Nucleic Acids Research, used computers to search all known proteins. The search identified the histone fold's presence in a large number of proteins that were previously considered unrelated to histones. They included enzymes and "transcription factors," proteins needed for genetic information to be expressed, and subsequently used, to produce other proteins essential for cells to function.
The histone fold appears to be one of the most ancient protein structures known today and has been preserved throughout millions of years of evolution. It is found in a diverse range of proteins, and the discovery paves the way for many new findings about its function.
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