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Biological Chemistry

First 3-D View Of The Body’s Pain-Sensing ‘Wasabi Receptor’

Biomolecular Structure: Snapshot of the TRPA1 ion channel, which senses chemical irritants, could lead to new pain and itch remedies

by Sarah Everts
April 13, 2015 | APPEARED IN VOLUME 93, ISSUE 15

09315-notw4-fig1acxdmicro-690.jpg
Credit: Nature
Cryo-electron micrographs (top) of TRPA1, which is 104 Å wide, were used to construct the ribbon structure of the chemical-irritant-sensing ion channel.

A wide variety of chemical irritants—including the molecules that give wasabi its kick and the toxic compounds that lend poison ivy its itch—activate the TRPA1 ion channel in the body. Switching on this channel leads to misery-producing pain, itch, or in the case of onions, tears. A structure of this important ion channel reported in Nature may pave the way to new analgesics that can tone down the protein when it signals too loudly (2015, DOI: 10.1038/nature14367).

09315-notw4-fig1ccxd-690.jpg
Credit: Nature

“TRP” ion channels (pronounced “trip”) permit the passage of cations across cell membranes in plants, animals, and fungi. Humans have a whopping 27 different types of the channels. In 2013, David J. Julius and his colleagues at the University of California, San Francisco, used cryo-electron microscopy to solve the first structure of a member of this important family: TRPV1, which gets activated by capsaicin, the molecule that makes hot peppers hot. Julius’s team has now gotten a glimpse of TRPA1 using the same technique.

Although the researchers’ 4-Å-resolution structure isn’t detailed enough to pinpoint individual atoms, it does provide general features of the protein’s shape in its closed, or “off,” conformation, Julius says. The team found that four TRPA1 subunits assemble to form the ion channel and that this foursome requires an unusual phospholipid called inositol hexakisphosphate to be stable in cell membranes.

The TRPA1 structure also revealed that 80% of the protein’s mass is located outside the channel’s membrane-spanning core, on either side of the cell membrane. Some of this mass is involved in binding a wide assortment of chemical irritants. Curiously, rather than forming typical transient bonds, certain compounds that trigger TRPA1 activate the channel by forming covalent bonds to some of its cysteine or lysine amino acid residues, says David E. Clapham of Harvard Medical School in an associated commentary (Nature 2015, DOI: 10.1038/nature14383).

Opening and closing of the TRPA1 pore is likely regulated, at least in part, by a collection of so-called ankyrin repeats, amino acid sequences that hang from the channel down into the cell’s interior and form a docking platform for regulator proteins, Julius says. This docking platform has “a propeller-like structure, resembling the backs of four armadillos,” Clapham adds.

“In the future, more-detailed structures of TRPA1 in different conformations will reveal regulatory features, such as why the channel becomes sensitized and desensitized to calcium, and perhaps more importantly, how channel function can be blocked to treat asthma, inflammation, and pain,” Clapham notes.

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