A 'dimmer switch' for genes - Protein that controls genes doesn't just turn on o

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A 'dimmer switch' for genes - Protein that controls genes doesn't

just turn on or off

01 Jul 2005 Medical News Today

A protein that was thought to simply turn genes on and off now looks

to be more like a cellular " dimmer switch, " researchers from Huntsman

Cancer Institute at the University of Utah, report in the July 1,

2005, issue of the journal Science.

The scientists showed for the first time that when certain parts of a

protein molecule are modified - flexible, randomly structured regions

believed to be only minor players in the protein world - they become

important in turning genes on and off, but in a way that resembles a

dimmer switch rather than an on-off switch.

Genes carry the code that produces proteins to carry out almost all

functions in a living organism. But some of these proteins also help

control when and where genes do their jobs. The new study deals with

how one such protein, named Ets-1, turns genes on or off.

Huntsman Cancer Institute scientists, led by Barbara Graves, Ph.D.,

professor and chair of the Department of Oncological Sciences at the

University of Utah School of Medicine, and doctoral student Miles

Pufall, studied Ets-1, a protein known as a transcription factor that

helps read genetic information. This factor serves as a cell's

librarian, helping find the right genetic instructions.

How much information the librarian provides, and how accurate that

information is, must be tightly controlled. Without the right

information, cells can't behave properly, and may, as in the case of

cancer, grow out of control. The connection between factors such as

Ets-1 and a number of cancers prompted the study of how it works.

One way proteins are controlled occurs after a cell creates a

protein. Graves illustrates this process by comparing protein

structure with beads on a string. " After the protein is made, it can

acquire what we call post-translational modifications, which are like

decorations on a beaded necklace. In this analogy, one person creates

a necklace using similar beads and then a committee comes along and

decorates it, putting a gold star here and a diamond there. These

modifications give the protein different properties. "

The " decorations " that were studied were phosphate molecules, which

previously had been shown to build up on proteins until a certain

number accumulated. The result, according to the study, has been

described in the past as a sharp on-off switch of protein activity.

" What we found was that each time we added a phosphate to a

particular unstructured region of Ets-1, there was an effect on the

protein's ability to bind to a gene. Binding was weakened, but it was

a gradual weakening. That isn't typical, " Graves says. " Instead of

acting like an on-off switch, it behaved the way a dimmer switch does

to regulate lighting in a gradual manner. "

In studying how this fine-tuning worked, they also discovered that

conventional wisdom failed to fully describe how proteins function.

It was known that proteins have regions with parts that are fixed in

space, with a definite structure, and parts that are randomly

positioned in space, like spaghetti strands. It was thought that the

structured regions did most of the work, while the unstructured

regions served only minor roles, such as tethering parts together.

" Scientists understand how a molecule works in part because we

understand the shape or structure, " Graves explains. " But what we

discovered takes us beyond knowing the structure. Our data were about

features that are not fixed in space, but that are flexible and

changing. "

The team used a nuclear magnetic resonance, or NMR, which allows

scientists to observe how the atoms of a molecule behave inside a

magnetic field. The Graves team found that unstructured regions of

the Ets-1 protein were affecting the structured regions in the work

of controlling genes. " In fact, " Graves reports, " the region's

unstructured nature appears to be an essential requirement. " NMR

showed that phosphate addition to this unstructured region caused a

gradual decline in DNA binding, gradually turning a gene off.

" One thing we didn't get was why Ets-1 worked differently before and

after phosphorylation [the addition of phosphate], " says

Pufall, " because as far as we could tell, the overall shape of the

molecule didn't change. "

" A protein molecule is not like a rock. It's more like Jell-O: it has

structure, it has shape, but it jiggles, " explains Graves. " We didn't

discover jiggling, but we were able to determine that the amount of

internal motion within a protein corresponds to the ability of a

protein to do its work. " Phosphorylation was found to decrease the

internal motion of Ets-1, reducing its activity.

According to Pufall, " Ets-1 provides a remarkable illustration of how

elegantly proteins are put together - forming a distinct shape, but

with the versatility to respond to the changing needs of the cell,

however subtle. "

The findings have long-term implications for the study of all

proteins, because, according to Graves, any protein has the potential

to be organized this way, with structured and unstructured regions

that work together.

Graves and Pufall conducted the study with doctoral student L.

, also of the Huntsman Cancer Institute; M. Lee, Hyun-

Seo Kang and Lawrence P. McIntosh at the University of British

Columbia; and Algirdas Velyvis and E. Kay at the University of

Toronto. The National Institutes of Health, U.S. Department of Energy

and the Huntsman Cancer Foundation funded the study.

Huntsman Cancer Institute

Department of Communication

and Public Affairs

2000 Circle of Hope, Room 5160

Salt Lake City, UT 84112

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