Folding upon binding: unique protein activation mechanism found by scientists at TSRI

February 04, 2002

A group of scientists at The Scripps Research Institute (TSRI) have solved the structure of two critical human proteins that are normally unstructured in the cell, but fold synergistically so that together they form an active biological structure.

The structures themselves may one day lead to new therapies, since the proteins are important regulators of genes essential for development and reproduction and are implicated in cancer and other diseases. Furthermore, the work provides biologists with a first glimpse of a synergistic folding mechanism--which may be a commonplace occurrence in the cell.

The two proteins are a nuclear receptor coactivator and the general transcription coactivator called CBP, and their structure is reported in the current issue of the journal Nature by a group led by Peter E. Wright, Ph.D., who is Professor and Chairman of the Department of Molecular Biology and Cecil H. and Ida M. Green Investigator in Medical Research at TSRI.

"This [synergistic folding] is something that has never been seen before," says Wright. "We have always thought about proteins in terms of their shape, their 3-D fold. It was always assumed that the structures of proteins are responsible for their biological functions."

"We can no longer just equate structure with function," he says.

If cells are the tiny factories of life, proteins are the workers, machines, bricks, and mortar of those factories. For years biologists have solved the structures of proteins as a way of elucidating their mechanisms and understanding life on the molecular scale.

But it is now recognized that many of the proteins in the human genome are normally unstructured in the cell. By some estimates, 30 to 40 percent of the human genome codes for proteins that have either large unstructured regions or are entirely unstructured and yet are biologically functional, and there is growing evidence that much of biology is carried out by these "intrinsically unstructured proteins."

The structure, solved by Wright and his colleagues through nuclear magnetic resonance spectroscopy, demonstrates that these two intrinsically unstructured transcriptional proteins fold synergistically and become active when brought together, suggesting a novel mechanism by which this type of protein may carry out biological functions.

The structures of the proteins are also interesting from the point of view of basic biological research because they are important players in the nuclear hormone response. As critical regulators of the nuclear hormone response, these proteins provide a potential target for therapeutic intervention, specifically in certain forms of breast and cervical cancers.

The nuclear hormone response regulates the expression of genes that are essential for everything from tissue growth and development to sexual reproduction. Such important genes must be tightly regulated, and the body accomplishes this by employing transcription factors.

Transcription factors are the proteins that bind to the DNA of the genes and regulate their expression by recruiting the polymerase molecule--the cellular machine that transcribes DNA into RNA. The cell cannot initiate transcription until the polymerase is recruited by these factors.

In the nuclear hormone response, one of the important participants is the protein p160, which associates with the CBP/p300 protein. Synergistically folded CBP/p300 and p160 are "coactivators" of transcription because they make the DNA available for transcription as well as recruit the polymerase molecule.
The research article "Mutual synergistic folding in recruitment of CBP/p300 by p160 nuclear receptor coactivators" is authored by Stephen J. Demarest, Maria Martinez-Yamout, John Chung, Hongwu Chen, Wei Xu, H. Jane Dyson, Ronald M. Evans, and Peter E. Wright and appears in the January 31, 2002 issue of Nature.

The research was funded by the National Institutes of Health and The Skaggs Institute for Chemical Biology.

Scripps Research Institute

Related DNA Articles from Brightsurf:

A new twist on DNA origami
A team* of scientists from ASU and Shanghai Jiao Tong University (SJTU) led by Hao Yan, ASU's Milton Glick Professor in the School of Molecular Sciences, and director of the ASU Biodesign Institute's Center for Molecular Design and Biomimetics, has just announced the creation of a new type of meta-DNA structures that will open up the fields of optoelectronics (including information storage and encryption) as well as synthetic biology.

Solving a DNA mystery
''A watched pot never boils,'' as the saying goes, but that was not the case for UC Santa Barbara researchers watching a ''pot'' of liquids formed from DNA.

Junk DNA might be really, really useful for biocomputing
When you don't understand how things work, it's not unusual to think of them as just plain old junk.

Designing DNA from scratch: Engineering the functions of micrometer-sized DNA droplets
Scientists at Tokyo Institute of Technology (Tokyo Tech) have constructed ''DNA droplets'' comprising designed DNA nanostructures.

Does DNA in the water tell us how many fish are there?
Researchers have developed a new non-invasive method to count individual fish by measuring the concentration of environmental DNA in the water, which could be applied for quantitative monitoring of aquatic ecosystems.

Zigzag DNA
How the cell organizes DNA into tightly packed chromosomes. Nature publication by Delft University of Technology and EMBL Heidelberg.

Scientists now know what DNA's chaperone looks like
Researchers have discovered the structure of the FACT protein -- a mysterious protein central to the functioning of DNA.

DNA is like everything else: it's not what you have, but how you use it
A new paradigm for reading out genetic information in DNA is described by Dr.

A new spin on DNA
For decades, researchers have chased ways to study biological machines.

From face to DNA: New method aims to improve match between DNA sample and face database
Predicting what someone's face looks like based on a DNA sample remains a hard nut to crack for science.

Read More: DNA News and DNA Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to