Report

On

Selectivity of Potassium Channel (By Abhishek Das, 20131056)

In 1998 leading biochemist Roderick MacKinnon and his team were successful

in not only determining the structure of an ion channel for the first time in high resolution but

also realizing how the particular class of proteins function by looking at it at the atomic level.

For this ground-breaking work on “structural and mechanistic studies of ion channels”

particularly potassium channels MacKinnon was honoured with the Nobel Prize in Chemistry

in 2003.

Ion channels are basically a class of proteins that are present as tiny pores on

the surface of all living cells in between the cell membrane. These channels allow the

exchange of potassium, calcium, sodium and chloride ions between the oily substance inside

the cell and the water outside it. Rapid-fire opening and closing of these channels releases

ions, thus moving electrical impulses from the brain in a wave to their destination in the body.

Ion channels exhibit the following three essential properties: i) they conduct ions rapidly, ii)

many ion channels are highly selective, which means only certain ion species flow while others

are excluded, iii) their function is regulated by processes known as gating, i.e. ion conduction

is turned on and off in response to specific environmental stimuli.

In 1952 Hodgkin and Huxley gave a working principle for the voltage-gated

potassium channels but were unable to provide any kind of structural explanation.

MacKinnon studied the interaction of the voltage-gated potassium channel with a specific

toxin derived from scorpion venom applying methods of protein purification and X-ray

crystallography. He worked on finding the structure of the potassium channels in particular

which are of particular importance to the nervous system and enable only potassium ions to

cross the cell membrane. He discovered that the signature sequence (amino acids) were

conserved in the tetrameric K+ channels in the tree of life which helped in achieving a rapid,

selective K+ conduction across the cell membrane. It was surprising how high conduction rates

and high selectivity were achieved at the same time.

With the help of X-ray crystallography, MacKinnon and his colleagues were

able to determine the 3-D structure of a potassium channel from the bacteria, Streptomyces

lividans. In the K+ channel, four subunits surround a central ion pathway that crosses the cell

membrane. The ion pathway was wide near the centre of the pathway forming a cavity thus

allowing a K+ ion at its centre. Also the pore helices were arranged as if to stabilize the K+ ion

in the cavity. One of the important functions of the K+ channels is to lower the membrane

barrier, created due to the oily interior of the cell, by hydrating a K+ ion deep inside the

membrane and by stabilizing it with charges at the end of α-helix.

Given the structure of the K+ channels it became easier to understand the

reasoning behind the conservation of such channels. In the signature sequence of the

channel, the alternating glycine amino acids permit the required dihedral angles; the

threonine hydroxyl oxygen atom co-ordinates to a K+ ion and the side chains of valine and

tyrosine are directed into the protein core surrounding the filter to impose geometrical

constraints. It forms a narrow tube consisting of four equally spaced K+ binding sites where

each binding site is a cage formed by eight oxygen atoms on the vertices of a cube-like shape.

The oxygen atoms surrounding the K+ ions in the selectivity filter are arranged in a similar way

as the water molecules that surround the hydrated K+ ion in the cavity. This portrays a clear

view of how the energetic cost of dehydration of the K+ channel is borne by the binding sites

in the filter. Thus from the recorded data MacKinnon proposed that the Na+ ion is too small

for these K+-sized binding sites, so its dehydration energy is not compensated therefore

exhibiting selectivity of K+ channels.

MacKinnon did further studies on the stoichiometric analysis of the ion

conduction rate to figure out the mechanism of ion movement through the filter and found

out how two K+ ions move through the channel at a time. Thus his research led to the

explanation of the structure and functioning of the voltage-gated ion channels in cells and

helped in the progress of numerous processes in biology in general.

References and Citations

Potassium Channels and the Atomic Basis of Selective Ion Conduction (Nobel Lecture)

(Roderick MacKinnon)

https://en.wikipedia.org/wiki/Potassium_channel#Selectivity_filter

http://www.osti.gov/accomplishments/mackinnon.html