On Faculty:
Biological Clues Folded Into Ancient Proteins


Emil Venere
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Homewood News and Information

     Biophysicists are homing in on a fundamental fold of
protein--essential for a multitude of life processes--that
apparently has been handed down from the beginning of life on
Earth.

     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,
said Evangelos Moudrianakis, one of the biophysicists involved in
the work.

     Scientists call the structure the "histone fold," a specific
three-dimensional arrangement of 65 amino acids, 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 they are lined up by their histone-fold regions,
they appear strikingly similar. 

     A scientific paper on the discovery was written by Gina
Arents, a research associate in the Hopkins Biology Department,
and Moudrianakis, a biology professor. The findings were reported
in the Nov. 21 issue of Proceedings of the National Academy of
Sciences. 

     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 paper, the researchers
described the structural characteristics of the histone fold and
analyzed 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
different biological functions but appear to have evolved from a
common and simple protein ancestor, the histone fold.  

     An earlier, related study was initiated by the Hopkins
scientists, along with former graduate student Andreas D.
Baxevanis, who is now at the National Institutes of Health. Those
earlier findings 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.

     In 1991 the biologists 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.

     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.