Ion Channel Close-Up | November 19, 2007 Issue - Vol. 85 Issue 47 | Chemical & Engineering News
Volume 85 Issue 47 | p. 9 | Latest News
Web Date: November 19, 2007

Ion Channel Close-Up

Structure reveals intimate role for lipids
Department: Science & Technology
Support System
A view of the voltage-gatedK+ (green) channel (backbone trace is purple) from outside the cell. Lipids (gold) with phosphate groups (oxygen is red) stabilize gaps between voltage sensors.
Credit: © 2007 Nature
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Support System
A view of the voltage-gatedK+ (green) channel (backbone trace is purple) from outside the cell. Lipids (gold) with phosphate groups (oxygen is red) stabilize gaps between voltage sensors.
Credit: © 2007 Nature
Paddles (red) are transferable between different voltage-sensing proteins.
Credit: Courtesy of Roderick MacKinnon
8547notw1_crystal02cxd
 
Paddles (red) are transferable between different voltage-sensing proteins.
Credit: Courtesy of Roderick MacKinnon

A HYBRID ION CHANNEL has given researchers the most detailed look yet at the chemical structure and interactions underpinning the function of these membrane-embedded proteins (Nature 2007, 450, 370 and 376). The new structure, determined by X-ray crystallography, was made possible by transplanting a key component from a related channel protein. It shows that the lipid bilayer surrounding the channel plays an important role in its structure and function.

Voltage-gated potassium ion channels are central to fundamental biological processes such as muscle contraction. They balance the ebb and flow of charge in nerve cell membranes by opening their gates in response to shifts in charge distribution. The structural basis for the mechanism of voltage detection, however, remains controversial. One theory, developed by Rockefeller University biophysicist and crystallographer Roderick MacKinnon, is that a portion of the voltage sensor, known as the paddle, moves at the cell's protein-lipid interface to mediate gating.

The new structure provides chemical details for this mechanism by supplying the first close-up of a mammalian voltage-gated K+ channel.

Kenton J. Swartz and colleagues at the National Institute of Neurological Disorders & Stroke at NIH paved the way for the new structure when they found that paddles can be swapped between different voltage-sensing proteins while retaining biological activity. The vulnerability of channels to certain protein toxins transfers along with the paddle, Swartz says. That result strongly indicates that the paddle "acts more or less independently as a self-contained mobile structure," says Senyon Choe, professor of structural biology at the Salk Institute.

MacKinnon's team transplanted paddles from one rat voltage-gated K+ channel into another to prepare a hybrid channel for X-ray studies. The team used mixtures of lipid and detergent to obtain crystals of the channel. Unlike previous structures, this new one makes clear how surrounding lipids help to stabilize membrane-spanning K+ channels.

In the new structure, the lipids assume a bilayer-like conformation and pack the gaps between the protruding voltage sensors in the channel protein. Previous work indicated that K+ channels stabilized by lipids devoid of negatively charged phosphate groups do not function properly. The new structure explains this observation by showing that an arginine side chain protrudes from the voltage sensor and is positioned to interact with lipid phosphate groups. Previous functional studies focused on how this and other arginines in the structure might help sense the voltage. The current study reveals the role neighboring lipids might play. "It was an oversimplification to think that the protein was doing the job alone," MacKinnon says.

With the clarifications the new studies provide, "I think we are now left with the most challenging, yet delightful, part of the structural interpretations: how each part moves and on what time scales," Choe says. To that end, MacKinnon plans to obtain a snapshot of a closed K+ channel to complement the open conformation in the current structure.

 
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