It turns out that cholesterol is vital to sensing bitter tastes

Humans have the ability to sense 5 different tastes – sweet, salty, sour, umami, and bitter – through specialised taste receptors located in the taste bud cells of the tongue.

When it comes to foods that leave a bitter taste in the mouth, humans have 26 different taste receptors capable of detecting more than 1,000 bitter tastants. Now, researchers have revealed exactly how we perceive those bitter tastes, in a new paper published in Nature.

Scientists solved the protein structure of one of the bitter taste receptors, TAS2R14, determining where bitter-tasting substances bind and how they activate it. They also reveal that cholesterol gives TAS2R14 a helping hand in activation, raising questions about its role with TAS2R14 in other parts of the body.

“Scientists know very little about the structural make up of sweet, bitter, and umami taste receptors,” says Dr Yoojoong Kim, a postdoctoral researcher in the University of North Carolina School of Medicine in the US, and first author of the paper.

“Using a combination of biochemical and computational methods, we now know the structure of the bitter taste receptor TAS2R14 and the mechanisms that initialises the sensation of bitter taste in our tongues.”

TAS2R14 is a G protein-coupled receptor (GPCR). When a bitter compound comes into contact with TAS2R14 it wedges itself into a specific spot on the receptor called an allosteric site. This causes the protein to change its shape and activates the attached G protein.

A series of biochemical reactions are triggered within the taste receptor cell. The cell then sends signals through nerve fibres to an area of the brain called the gustatory complex, where the brain processes and perceives the signals as bitterness.

The new structure also revealed a unique feature of TAS2R14: cholesterol slots to another binding site called the orthosteric pocket.

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Representative cryogenic electron microscopy (cryo-EM) maps (left) and models (right) for TAS2R14 (green) coupled to the Ggust G Protein (subunits in purple, pink, sky blue, yellow, and grey). Credit: Kim et al (2024)

“Through molecular dynamics simulations, we found that the cholesterol puts the receptor in a semi-active state, so it can be easily activated by the bitter tastant,” says Kim.

Previous studies have discovered that TAS2R14 is also found outside of the mouth, suggesting it has functions beyond its role in bitter taste perception.

Research has shown that bile acids, which are created from cholesterol in the liver and have similar chemical structures to it, can bind to and activate TASR14. How and where they do this has remained unclear, but the new finding suggests that it might be occurring in the same orthosteric pocket as cholesterol.

While the exact role of bile acids and cholesterol in TAS2R14 remains unknown, it may play a role in the metabolism of these substances or in relation to metabolic disorders such as obesity or diabetes. The researchers are planning future studies to investigate the function these proteins may have outside of the mouth.

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