Jay T. Groves wants to know how organization of proteins within the cell's plasma membrane affects their functions.

“All metabolically active life relies on membranes,” says Jay Groves, an HHMI investigator at the University of California, Berkeley. Apart from various kinds of phospholipids, and related molecules like cholesterol, plasma membranes teem with proteins. Some proteins are inserted into only one side of the membrane, acting as a beacon for other proteins that need to find the membrane. Some jut all the way through the membrane, such as receptors that detect signals on one side of the membrane and send them along on the other. And some proteins help shuttle materials—like water, nutrients, or charged particles—across.

One branch of membrane research focuses on studying the channels that allow charged ions to pass through a membrane, sending fast electrical signals. These channels allow, for example, the firing of neurons by switching between open and closed depending on the charge difference they sense across the membrane.

“Without this switch life couldn't ever have been bigger than single-celled organisms,” says MacKinnon, “because you couldn't transfer information across the organisms fast enough to make any appreciable behavior.”

Long before the structures of these proteins could be fully imagined, scientists could use probes that measure electric currents to detect ions moving through the channels and calculate basic properties of when and how they functioned.

“At the beginning, ion channel work was, essentially, basic electrophysiology,” says Chris Miller, an HHMI investigator who studies ion channels at Brandeis University and who mentored MacKinnon during his undergraduate and postdoctoral training. “And then the whole thing changed when Rod MacKinnon broke through this structural barrier, which was as much a psychological one as a technical one.”

Most of the scientists who have determined membrane protein structures since then rely on x-ray crystallography to piece together how the atoms in a protein are arranged. They shine a beam of x-rays at the protein and measure how they are diffracted. For this technique to work, many copies of the protein must be isolated from a cell and arranged in a symmetrical crystal. Since membrane proteins tend to fall apart unless they're embedded just so in the membrane, this is tricky. Researchers must surround the proteins with fatty detergents to keep them arranged correctly in solution. It's as much luck as it is hard work, says Miller.

“If you've prayed to the right gods that day, the protein crystallizes and then you can play games from there,” he says. Using this method, scientists have illuminated some of the major protein players in the membrane: pores that allow water through, channels that allow ions to move across, and membrane-embedded receptors that pass signals between cells.

Some basic questions about membrane protein structure remain unanswered. Each new structure gives scientists a better picture of how proteins fold into the membrane and how to predict what a protein will look like based on its amino acid sequence.

Noah Berger/AP, ©HHMI

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