January 18, 2006

Structure of a Mammalian Ion Channel

A research group led by Nobel Prize winner Roderick MacKinnon has determined the three-dimensional molecular structure of a mammalian "ion channel," a type of cell-membrane protein that allows ions to pass in and out of cells. The structure is an important step in understanding how ion channels produce and control cellular electrical activity, which regulates hormone secretion, controls heartbeats, and drives the nervous system.

The structure is described in two papers in the August 5, 2005, edition of Science, including the cover article, and is based on data collected at NSLS beamlines X25 and X29, and the Swiss Light Source. The research group used an ion-channel protein crystal derived from rat brain cells. This particular type of channel is selective to potassium ions, meaning it "knows" how to reject similar ions, such as sodium.

The cover of the August 5, 2005, issue of Science, which features the MacKinnon group's ion channel structure.

"Potassium ion channels exist in nearly every type of organism, but most of what we know about their molecular structures is the result of studying channels derived from non-mammalian cells. This has been valuable, but has left some questions about how the structure of the channel relates to its behavior," said MacKinnon, a neurobiologist and biophysicist at The Rockefeller University's Howard Hughes Medical Institute. "We hope that our study will fill in some of these gaps and lead to a better understanding of potassium-ion channels."

The x-ray data reveal that the main portion of the channel consists of four molecular "subunits" that fit together like a three-dimensional puzzle. These parts form key channel features, such as the "pore," the channel's circular opening, and four voltage-sensor paddles attached to the pore, which detect the voltage change in the membrane and signal the pore to twist open or closed. In its overall shape, the channel resembles a pinwheel from the top down and, from the side, an hourglass.

When potassium ions, which carry a positive charge, approach the cell membrane, they trigger a slight change in the membrane's voltage, which is then sensed by a nearby ion channel that, in turn, opens to allow the ions through. The ions then pass through the pore, travel partway through the channel, and enter the cell's inner fluid, called the cytoplasm, through side portals located on the channel's narrow neck. Thus, the ions interact directly with the top portion of the channel only, which begins just outside the cell (the "extracellular" area) and dips below the cell membrane into the inner-cell (intracellular) area.

Crystal structure of the potassium-ion channel. The channel contains four subunits (shown in red, cyan, green and yellow). The region within the membrane contains a pore, which conducts the potassium ions, and voltage sensors, which open the pore in response to changes in the membrane voltage. Inside the cell, the T1 domain forms a docking platform for the beta subunit (blue), which has four active sites (orange). Figure courtesy of Rod MacKinnon.

The lower portion of the channel contains two more main components: the "T1 domain," located below the side portals, and the "beta (ß) subunit," which is nested within T1. The exact functions of the ß subunit and the T1 domain are not fully known. The ß subunit consists of four identical enzyme "active sites" - places that other molecules or ions can bind to and produce a chemical reaction involving the transfer of a hydrogen atom. The T1 domain appears to act as a docking station that tethers the ß subunit to the rest of the structure.

"We think that the ß subunit has additional functions, and are hoping that further examination of this channel's crystal structure will lead us to those answers," said MacKinnon.

This study was supported by the National Institutes of Health and the Howard Hughes Medical Institute.

SCIENCE WRITER: Laura Mgrdichian