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Researchers Reveal Architecture Of Protein From First Known Oncogene

Date:
February 18, 1997
Source:
Harvard Medical School
Summary:
Twenty-seven years after the first human cancer-causing gene was discovered, scientists can finally take a look at Src, the protein it produces. This work will help drug designers understand Src in atomic detail.

Researchers
Reveal Architecture Of Protein From First Known Oncogene


BOSTON--Twenty-seven years after the first human
cancer-causing gene was discovered, scientists can finally take a
hard look at Src, the protein it produces. Researchers led by
Howard Hughes investigator Stephen Harrison and Harvard Medical
School colleague Michael Eck will display the crystal structure
of human Src in the February 13 Nature.

This work, illuminating the highest resolution structure ever
of a protein of its class, will help drug designers understand
Src in atomic detail. Since Src closely resembles eight other
members of its family, this long-sought structure establishes
general principles for how these complex proteins fold up their
amino acid chain to regulate their important but dangerous
biochemical work in the cell. Indeed, a structure of a second
family member published by other researchers in the same issue of
Nature confirms these principles.

Rational drug design has been much touted as the smart, new
way to find drugs more quickly, but the driving force behind it
is really structural biology. Without a 3-D view of how the atoms
of a protein implicated in disease arrange themselves in
molecular space, rational drug designers are poking in the dark,
trying to shoot bullets at a target they can1t see. Many
researchers in academia and industry have tried to elucidate the
structure of Src, and several pharmaceutical companies are
searching for inhibitors for tyrosine kinases, the class of
enzymes of which Src is a flagship member. These still elusive
inhibitors could treat not only cancer, but potentially
transplant rejection and autoimmune diseases, as well.

The protein Src comes as a Dr. Jeckyll-Mr. Hyde pair. Its
benevolent form helps control growth and division, but mutations
can turn it into an oncogene. This villain often enters cells via
a virus, the context in which it was discovered in 1970. Since
this Nobel-prize-winning research, Src has become a household
name among bioscientsts. 3Src is a granddaddy of famous
proteins,2 says Eck, assistant professor of biological chemistry
and molecular pharmacology. In hundreds of studies, researchers
have zoomed in on its normal and subverted functions in ever
greater detail.

Normal Src conveys growth signals from the cell1s outside to
its inside. It does so by tacking phosphate groups onto tyrosine
amino acids in other proteins, in a process called
phosphorylation. Previous research suggested that Src, much like
a switch, occurs in the 3off2 state most of the time and that
stimulation flips it to the 3on2 state. Scientists also have
known that cancer-causing mutations lock Src in the 3on2
position, sending it into a growth-promoting frenzy.

But how exactly does this work? Src must be a sort of
multiplex switch, for it receives different types of input and,
in response, turns on or off. More than scientific curiosity,
this question is key to attempts to interfere therapeutically,
says Harrison. 3Now at least we have a first view of this class
of switch,2 says Harrison, who is also professor at Harvard.

Most people think of proteins simply as tiny blobs. But when
Eck, Harrison, and postdoc Wenquin Xu scrutinized the structure
of Src, they realized that it is a formidable product of
nano-engineering. 3Src is a fancy little machine. It has an
incredible amount of information technology built into a tiny
package, where every bit matters and is used creatively,2 says
Eck.

Src consists of four lobes: Two lobes make up the kinase
performing the protein1s ultimate function, and two others,
dubbed SH2 and SH3, regulate the kinase and help Src travel to
its site of action within the cell. Previous research had
visualized parts of Src, but this is the first study that puts
them together into a broader vista of how the parts interact. To
their surprise, the researchers found that several mechanisms are
at work simultaneously to keep Src idle, says Eck.

For one, the four lobes are connected by short 3linker2
stretches, like pearls on a string. The crystal structure reveals
that when Src is in the 3off2 state, the string is curled up into
a compact ball, with the molecule1s tail end wrapped around the
SH2 lobe in a tight embrace. This crunched conformation pulls
shut the cleft between the two kinase lobes, the site where the
enzymeĐwhen activeĐengulfs and phosphorylates its target.

For another, the SH3 domain turns its binding surface inward
and snuggles up against the surface of one of the stretches
linking two lobes. This atomic interaction in effect hides SH3
from the proteins it would bind in the active state of Src,
preventing SH3 from facing outward, where it could encounter
those proteins. The tail reaching around SH2 similarly locks away
this lobe. Thirdly, a crucial stretch of protein helix, located
above the active site, is squeezed out of position.

Together, these and more mechanisms serve to keep a lid on
Src. At the same time, they keep it poised to spring into action,
much like a Jack-in-the-box. That is because these intramolecular
ties are weak, says Eck. When a growth signal comes along, it
probably offers stronger, more attractive binding surfaces for
one of Src1s many sensitive spots, unraveling and activating the
protein.

The details of how Src gets turned on require still more
research, Eck adds. But the structure has already shown that some
of the known mutations making Src cancerous disturb this web of
inhibitory ties, letting the Jack permanently out of the box.
Says Eck: 3Src looks like an oncogene product waiting to happen.
Because everything is so interdependent, you can imagine that
disrupting any of its internal ties might cause the house of
cards to fall.2

Editors, please note: a four-color print or electronic file of
the Src structure are available on request. --END--


Story Source:

The above story is based on materials provided by Harvard Medical School. Note: Materials may be edited for content and length.


Cite This Page:

Harvard Medical School. "Researchers Reveal Architecture Of Protein From First Known Oncogene." ScienceDaily. ScienceDaily, 18 February 1997. <www.sciencedaily.com/releases/1997/02/970218123523.htm>.
Harvard Medical School. (1997, February 18). Researchers Reveal Architecture Of Protein From First Known Oncogene. ScienceDaily. Retrieved August 23, 2014 from www.sciencedaily.com/releases/1997/02/970218123523.htm
Harvard Medical School. "Researchers Reveal Architecture Of Protein From First Known Oncogene." ScienceDaily. www.sciencedaily.com/releases/1997/02/970218123523.htm (accessed August 23, 2014).

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