CHAMPAIGN, Ill. — Using computer simulations and experimental
results, researchers at the University of Illinois at Urbana-Champaign
and the University of Arizona have identified a key component of the
gating mechanism in aquaporins that controls both the passage of water
and the conduction of ions.
Aquaporins are a class of proteins that form membrane channels
in cell walls and allow for water movement between a cell and its
surroundings. A number of aquaporins, including aquaporin-1, have been
found to function as ion channels, as well.
"Understanding the molecular mechanism behind gating in
membrane channels could lead to more effective protein engineering,"
said Emad Tajkhorshid, a professor of biochemistry at Illinois and a
researcher at the Beckman Institute for Advanced Science and
In work funded by the National Institutes of Health,
Tajkhorshid and co-workers show that the same protein can be used as a
water channel or an ion channel depending on the signaling pathway
activated in the cell. The scientists report their findings in the
September issue of the journal Structure.
Taking advantage of the known crystal structure of aquaporin-1 and the
power of molecular dynamics simulations, the researchers explored the
central pore as a candidate pathway for conducting ions. Gating of the
central pore is controlled by cyclic guanosine monophosphate, a
signaling nucleotide inside the cell, which induces a conformational
change in one of the aquaporin loops (loop D).
"This loop is very flexible, has four positively charged
arginine residues in a row, and extends into the central pore,"
Tajkhorshid said. "We believe the cGMP interacts with loop D,
facilitating its outward motion, which triggers the opening of the
The work highlights a close interaction between simulation and
experiment. Based on their simulation results, the researchers designed
a mutant in which two arginines in loop D were replaced by two
alanines. In laboratory experiments performed at Arizona, the
substitution caused an almost complete removal of ion conduction, but
had no appreciable effect on water passage.
"Knowing the mechanism gives us a new handle to control the
opening or closing of the central pore," Tajkhorshid said. "By
modifying the pore-lining residue, or altering the length of loop D
that gates the pore, we can shut down the ion conductivity completely,
or engineer new aquaporins that can be opened more easily or have a
higher ion conduction rate once open."
University of Illinois at Urbana-Champaign. September 2006.