October 1996
Mike Blaber (left) and Tim Logan examine a model of the FK 506 Binding Protein.
The FKBP, as it's called, catalyzes the folding process for other
proteins.
Solving the mystery of protein folding
could help fight AIDS, cancer and aging
By John S. Cole
FSU Communications Group
Mike Blaber and Tim Logan are on a five- year mission to boldly go where
no one has gone before.
This trek won't take them into deep space, but the two FSU biochemists hope
their fantastic voyage will help unlock the mysteries of protein folding.
On the surface, it may not sound like much, but according to Blaber and
Logan, assistant professors of chemistry at FSU, protein folding is the
most critical problem to face modern science since space flight.
Until proteins fold, they are little more than complex strings of amino
acids, Logan explained. Once folded, however, the proteins become
"active,"
keeping together many ingredients crucial to the proper function of all
living cells.
Scientists have yet to grasp exactly what causes proteins to fold or what
keeps them folded or why some stay folded longer than others. If they could
answer those questions, Blaber and Logan say, scientists would be a few
steps closer to curing many modern ills, from cancer to AIDS to Alzheimer's
Disease. The findings may one day even help slow the aging process.
"Understanding how proteins fold, in a real sense, would be greater
than sending a man to the moon," said Blaber, who earned his doctorate
from the University of California, Irvine, and came to FSU in 1994. "It's
that level of problem. I don't think that's an exaggeration."
It probably isn't. Scientists aboard the space shuttles have been grappling
with the same puzzle by growing protein crystals in space. Closer to home,
Blaber and Logan received five-year grants of $500,000 each from the National
Institutes of Health. "(Protein folding) probably is the major problem
in modern biochemistry," Logan said.
Proteins are fundamental components of all living cells and include many
substances, such as enzymes, hormones, and antibodies, necessary for an
organism to function properly. The way a protein folds determines how or
whether it will work.
"Proteins can be thought of as little tiny machines in a sense,"
said Blaber. "If we understood more about how these little machines
work we could change them to do things that they wouldn't otherwise
do."
The possibilities range from disabling cancer cells to making oil and plastic
biodegradable, said Logan, who earned his doctorate from the University
of Chicago. He too was hired by FSU in 1994.
"What you would like to be able to do is say, 'I have this problem,
and I would like to design a protein that will solve that problem,'"
he said. "It becomes almost an engineering problem at that point, but
to do the engineering problem you need to know how strong your girders are.
"You need to know what kind of cement you have and how long that cement
is going to be stable and strong. Those are the questions that we're trying
to answer."
The chemists work closely together, sharing information, equipment and student
help. But they are actually working on separate parts of the same puzzle.
Logan seeks to discover what makes proteins fold and why they fold in different
ways.
Using a technique called nuclear magnetic resonance spectroscopy, Logan
has isolated fragments of the FK 506 Binding Protein. The FKBP, as it's
known in science circles, is one of a handful of proteins that catalyzes
the folding process of other proteins.
Learning more about the way the FKBP folds, Logan said, should tell scientists
a lot about the way most other proteins fold.
Meanwhile, Blaber is using heat to test and measure the stability of a protein
called the Fibroblast Growth Factor.
"This is a protein which is able to stimulate a variety of different
types of cells to divide and grow," he said.
It is particularly effective on blood vessels, he said.
"There have been experiments where they've taken a sponge for example
and soaked it in this growth factor, surgically inserted it next to the
heart, and caused blood vessels from local arteries to grow into the heart
and supply it with more blood," he said.
There is only one problem. The protein in its natural state is unstable.
"That means that after a very short period of time, the protein's
unfolded,"
Blaber said. "Once it's unfolded it doesn't work."
If he could figure out what makes proteins stay folded and how to control
it, Blaber could make proteins stay active for weeks or even months as opposed
to minutes, he said.
"That way when you implant this thing... you only have to do it once,"
he said. "You don't have to go back in and repeat the implant every
week."
Both projects are in preliminary stages, the scientists said. But early
results point to a promising future.
"We're just trying to add in pieces to a larger puzzle," Logan
said.
"Down the road there will be some big advances, "Blaber said."
(I hope) I'll be able to look back and say I was a significant contributor
to this significant project mankind undertook."