A breakthrough in taste receptors could open the door to new culinary experiences

The umami taste receptor in pufferfish grips both mirror-image forms of an amino acid, held shut by two tiny molecular latches.

Savory taste comes down to amino acids, and every amino acid comes in two mirror-image forms. The human savory receptor answers to one of them and ignores the other. In pufferfish, researchers have now mapped a receptor that grips both.

That flexibility isn't sloppiness. Two small hooks inside the protein hold it closed around a molecule that doesn't quite fit. That widens what the fish can taste without altering the part that touches the food.

Atsuko Yamashita's team at the Institute for Protein Research at The University of Osaka solved the structure with colleagues at Okayama University and the RIKEN SPring-8 Center.

They pictured the end of the receptor that grabs food molecules, not the whole protein sitting in a cell membrane.

Taste receptors pick one amino acid shape

Most amino acids come in two versions built from the same atoms in the same order, mirrored the way a left hand mirrors a right. Chemists call them L and D. Proteins are built from the L-form, in every living thing.

That split runs through taste as well. The sweet and savory receptors belong to one family, TAS1R, and in people and mice they divide the work.

The savory side of that family is the umami taste receptor, and it answers to L-amino acids, mostly glutamate and aspartate. The D-forms go to the receptor behind a sweet tooth. One shape, one receptor.

Taste was the first place anyone found that the human body tells mirror images apart at all, about 140 years ago. Most large molecules in the body work that way, recognizing one mirror image and not the other.

The binding site was read in crystals

Most of these receptors refuse to fold properly outside an animal, which is why so few have ever been pictured. The two halves from the Japanese pufferfish Takifugu rubripes did fold, grown in insect cells for seven days at 68°F (20°C).

Yamashita's team crystallized the business end of the receptor and read its shape with X-rays. Each half turned out to be built like a Venus flytrap, two lobes with a cleft between them.

An amino acid drops into that cleft and the lobes close on it. The closing is the signal. An amino acid molecule of the wrong shape keeps the trap from shutting, so no taste message gets passed along.

The fish tastes both amino acid forms

Yamashita's team fed the receptor a long list of amino acids and watched two things. Whether each one stuck, and whether the full receptor in a living cell fired in response.

The L-forms worked, as expected. So did several D-forms. D-alanine and D-phenylalanine both stuck and both set off a small but real response. The human savory receptor tested alongside them stayed firmly one-sided.

But the grip wasn't equal. The protein held L-alanine about 11 times more tightly than D-alanine. Even so, D-phenylalanine produced a stronger response than the L-form did, despite binding more weakly.

L-glutamate and L-aspartate, the two molecules the human receptor likes best, stuck to the pufferfish protein and then triggered no noticeable response.

Two latches hold the cleft shut

Two pairs of side chains reach across the gap between the lobes and hook together, one near the bound amino acid and one further out. Neither touches the food. The researchers call them latches.

Yamashita's team swapped those side chains for the versions found in the human savory receptor, and the fish receptor turned picky, responding less to D-alanine.

A different single change went the other way, likely freeing a side chain to latch more easily, and that receptor lost its preference altogether.

None of those changes moved the binding much, with every value staying within twofold of the original. What changed was whether the closed shape held together long enough to send a signal.

"Normally, a receptor is unable to bind onto a molecule that is the wrong shape," Yamashita said.

"Discovering how the Tas1r1/Tas1r3 receptor structure acts like a latch, holding either an L- or D-amino acid molecule in place, is an exciting breakthrough in understanding how receptors can evolve to be more flexible."

Diet may explain the flexibility

Pufferfish eat mollusks and crustaceans, and those animals are unusually full of the D-form. D-alanine makes up 30 to 84 percent of the free alanine in crustaceans and in one large group of clams, where it helps them balance the salt in their bodies.

"We believe that the pufferfish's diet drives this molecular evolution. They eat a lot of mollusks and crustaceans, which contain high amounts of D-amino acids," Yamashita said.

"Generally, TAS1Rs are considered to discriminate L- and D-amino acids and sense only one of them. The ability to taste both forms may help the fish detect a wider range of savory amino acids in their foods."

What the crystals can't show

The structures cover the grabbing end of the receptor and nothing beyond it. One picture the team wanted never came at all: crystals of the L-phenylalanine version failed, so that shape is a computer prediction.

The authors can't yet explain why some molecules stick and then signal nothing.

On our side of the receptor family the gap is wider. Nobody has pictured a human sweet receptor with a D-amino acid sitting in it. So whether people's own mirror-image taste runs on latches or on something else stays an open question.

How rigid the rest of the family is has barely been tested in either direction.

For the field, the authors draw one design principle out of it. To widen what an animal can taste, evolution doesn't have to rebuild the part that grabs the food, and can add a hook somewhere else instead.

That is a usable idea for anyone formulating savory flavors, or feed for fish farms and livestock.

The full study was published in the journal Proceedings of the National Academy of Sciences.

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