April 03, 1998
Visualizing a Potassium Channel
This image shows a view of the four-fold axis of the KcsA potassium channel from the bacterium
Each of the channel's four identical subunits is shown in a different color. The center of the channel contains a potassium ion (green).
For many years, scientists have dreamed of knowing exactly how potassium channels are constructed, hoping that knowledge would tell them more about how such channels work.
Now, in two reports in the journal
a research team led
by Hughes investigator
at The Rockefeller University
unveils the crystal structure that shows the potassium channel's
"The crystal structure of the potassium ion channel presented by
MacKinnon and his laboratory is a dream come true for biophysicists,"
writes Clay Armstrong of the University of Pennsylvania in an
accompanying article in the April 3, 1998, issue of
Nearly 50 years ago researchers showed that electrical activity
in neurons is produced by subtle changes in the neuron's potassium
concentration. "Since then, it's been well established that the flow of
potassium ions is central to many different cellular processes," said
MacKinnon. Potassium currents in the brain, for example, underlie
perception and movement, and the heart's contraction relies upon the
steady ebb-and-flow of potassium.
To maintain the correct concentration of potassium, cells are
equipped with pore-like proteins that poke through the cell membrane.
These proteins, called ion channels or potassium channels, create sieves
through which potassium ions flow from inside to outside the cell.
During the last 10 years, molecular biologists have identified
many of the genes that produce the protein components of potassium
channels in a variety of organisms. Studies of those genes showed
researchers that potassium channels from different organisms were likely
to be structurally similar. Mutational analysis revealed more: "By
mutating those genes and looking at the functional consequences of those
mutations, we've been able to identify specific regions of potassium
channel proteins that serve crucial functions," MacKinnon said.
MacKinnon's laboratory and others around the world understood that a
complete picture of a potassium channel was badly needed. About 18
months ago, his group began trying to crystallize potassium channel
proteins from the bacterium
suitable crystals, they bombarded the protein crystals with x-rays at
the Cornell High Energy Synchrotron Source and collected the data that
would reveal the long-awaited structure.
Analysis of the x-ray crystallography data showed that the potassium
is shaped like a cone or "inverted teepee."
According to MacKinnon, the structure helps explain one of the great
biophysical mysteries - the chemical nature of the pore's main ion
conduction pathway. Potassium ions are normally surrounded by water.
When they slip into the channel, MacKinnon explains, the potassium ions
shed water. In order for this to happen, however, the pore must offer a
surrogate for water. "We can now see from the structure how that
happens," MacKinnon said.
Ion discrimination takes place in a region of the pore called the
selectivity filter. This area is called a filter because it is narrower
than the rest of the channel. "When a potassium ion enters the channel,
water floats away. Oxygen atoms from the protein then surround the ion,
making it more stable," MacKinnon said.
Scientists have also wondered why the sodium ion, which is smaller than
the potassium ion, doesn't jump into the potassium channel. Again, the
structure may provide insight: "It appears that the selectivity filter -
which is held in a very precise conformation - is more tuned for the
larger potassium ion," MacKinnon said.
In a second article in
MacKinnon's team sought confirmation
that the bacterial potassium channel they had crystallized was indeed
structurally similar to eukaryotic potassium channels found in humans.
MacKinnon and Hughes investigator
University had performed earlier experiments that showed that the deadly
scorpion toxin binds tightly to eukaryotic potassium channels. With this
information in mind, MacKinnon's group decided to see if the same toxin
would bind to the bacterial channel. "Our logic for this experiment was
that if the bacterial potassium channel really has the same structure as
the human potassium channel, then the bacterial channel should form a
binding site for the scorpion toxin," MacKinnon said.
In collaboration with Rockefeller colleagues Steven Cohen and Brian
Chait, MacKinnon's team showed that the scorpion toxin binds to a
slightly modified bacterial potassium channel, confirming that the two
channels are structurally similar.
Illustration: Roderick MacKinnon Laboratory/HHMI at The Rockefeller University