Report
Lead Investigator: Laura Kiessling


New Ligand Rounds Up Receptors and Tricks
Cells

by Dan Ferber

Bacteria find dissolved sugars to eat by sensing them with
receptors and swimming toward the source. Now, biochemists
have devised a new polymer that controls how well the bugs
swim toward the dissolved sugars by roping the receptors together
on the cell surface. Other polymers that work the same way could
kill tough bacteria that form biofilms, suppress antibody production
in humans with autoimmune disease or work as a vaccine to boost
human antibody production.

All cells respond to chemical cues
called ligands by grabbing them
with receptors, and relaying the message to its target in the
cell via a series of signaling proteins. Until recently,
researchers thought that cells responded when a single ligand
bound to a single receptor, setting off a cascade of signaling
reactions. But recently, researchers have been finding more
and more cells that respond only when a special ligand grabs
two or more receptors at the same time and forces them
together, says Laura Kiessling of the University of Wisconsin
in Madison, Wisconsin.

Researchers suspected that the response of the cell somehow
depended on how well the receptors were roped together,
Kiessling says. And if it did, they might be able to tweak the
behavior of the cell by roping together just a few receptors or
a whole gang of them.

To test this idea, the Wisconsin team used a polymer
ordinarily used to make tractor cabs and snowmobile parts. To
achieve this, they chemically adjusted the length of the
polymer and attached 1, 10, 25 or 50 molecules of a sugar
calle galactose to trigger bacteria to start hunting for food.
The researchers hoped that bigger polymers with more sugar
would trigger more receptors to clump, and the bacteria would
stop tumbling randomly and swim with a purpose - the precise
behavior that the bugs use to find food in nature, Kiessling
notes. But adds, "What's different is that we have
systematically controlled clustering. That's what's new."

To test this next idea, they measured the amount of time the
bugs spent tumbling randomly, versus the amount of time
they swimming with a purpose. With the larger polymers, it
didn't take much to set the bugs swimming - the polymers
loaded with 25 galactose molecules were 100-fold more
potent than just the sugar added alone.

What's more, when the researchers assayed chemotaxis, by
measuring how well the bugs could swim up into a capillary
tube loaded with attractant, they needed only 0.1 mM of the
50-mer, compared to 0.3 mM of the 25-mer and 1 mM of the
free galactose. These results indicate that the extent of the
cell's response can be controlled by how heavily the polymer is
loaded with sugar.

"They [the bacteria] think they are receiveing much more
galactose than they are", explains Kiessling. The work is to be
published in Chemistry and Biology.

Because many other cells, including B-lymphocytes in
humans, also respond when their receptors are roped
together, the results suggest that those responses can also
be controlled. In the case of B-cells, that means controlling
the level of antibody production. "What we've done for the
first time," concludes Kiessling, "is show that you can use a
synthetic ligand to systematically control a cellular response."