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Cells direct membrane traffic
by channel width, scientists say
Barlow, Life Sciences Editor
photo to enlarge
by Kwame Ross
Researcher Emad Tajkhorshid stands by a computer-generated
simulation of two aquaporins sliced open.
At left, a glycerol molecule lines up to enter a
glycerol channel (yellow), while at right a water
molecule approaches a slightly narrower channel
only it can fit through.
image to enlarge
— For a glycerol molecule, a measly angstrom’s difference
in diameter is a road-closed sign: You can’t squeeze through unless
you are a sleek, water-molecule-sized sports car, say scientists at
the University of Illinois at Urbana-Champaign.
The roadway is in aquaporins, a class of proteins that form trans-membrane
channels in cell walls in all forms of life. They allow for water movement
between the cell and its environment. A subfamily of aquaporins allows
slightly larger molecules, such as glycerol, to pass, too. In humans,
11 aquaporins have been identified, mostly in the kidney, brain and
lens of the eye. Impaired function has been implicated in a variety
Aquaporins are a target of scrutiny for the Theoretical
and Computational Biophysics Group at the Beckman
Institute for Advanced Science and Technology.
Using steered molecular
dynamics, Beckman researchers have solved a mystery that years of protein
crystallography couldn’t accomplish. Reporting in the August issue
of Structure, they show that the main structural difference that makes
an aquaporin a glycerol channel is a channel that is just a hundred-millionth
of a centimeter – an angstrom – wider than a normal water
So even if glycerol
molecules line up properly, as do water molecules to pass through a
pure water channel (as documented by researchers in the same lab in
2002), the slightly larger sugar molecule is out of luck. The point
of entry, known as a selectivity filter, is the most narrow, but there
are other tight barriers blocking the way as well, said Emad Tajkhorshid,
assistant director of research in the Beckman lab.
“Membrane proteins are difficult to crystallize,” he said.
“We don’t have the known structure of many of them. There
has been a lot of recent progress, and for aquaporins we’ve got
four structures available, which is really exceptional for membrane
For the new study, his team focused on two of them. “Both were
from the same bug, E-coli. One was a pure water channel. The other is
a glycerol channel,” Tajkhorshid said. “Structurally they
are similar. Researchers have tried to convert a water channel to a
glycerol channel, or the other way around, by mutating amino acids that
line the pore of the channel, but they have failed.”
The E-coli proteins studied were AqpZ, a water channel, and GlpF, a
glycerol channel. Side-by-side in computer-generated images the channels
appear virtually identical. The Beckman teamed pushed glycerol through
the channels, calculated the energetics and looked for barriers.
“Nature is using a very, very simple idea here,” Tajkhorshid
said. “Just by making a channel narrower, only water is allowed
to pass through the pure water channel; by making it a little bit bigger
in the other channel both glycerol, as well as longer, linear sugar
molecules, and water can permeate the channel.”
While channel sizes had appeared slightly different after crystallizing
the proteins in the past, researchers believed the channels could be
manipulated by inducing the surrounding amino acids to create a hydrophobic
or semi-hydrophobic lining required for glycerol passage. Success in
doing so could have created new targets for drug therapies.
However, it turns out, the amino acids are the same around both channels,
Tajkhorshid said. So his team now is looking beyond the amino acids
directly lining the channel to find what it is that forces changes in
The same principles, he added, likely apply to all selective protein
channels. Understanding the principles could provide new, effective
pharmaceutical targets to control the channels to help treat disease.
Study co-authors were group director Klaus Schulten and Yi Wang, a doctoral
student in molecular and cell
biology. The National Institutes of Health funded the study, which
involved the use of supercomputers at the Pittsburgh Supercomputing
Center and the National Center for
Supercomputing Applications at Illinois.