Understanding Taste by Studying the Protein-Protein Interactions of Taste Receptors

Understanding the underlined cellular mechanisms of human taste is an essential step for designing new food products and for improving the taste of food, nutraceutical, food supplements and even pharmaceutical products. Moreover, taste mechanisms have been evolutionary linked with protective mechanisms against hazardous compounds, thus understanding how taste works at a molecular level and its top-down effects can trigger the discovery of new therapeutic methods or identify potential novel therapeutic effects for compounds of known taste.

Fig. 1. Summary Figure of Taste Receptors and their Features. This Figure was generated by modifying figures from Pallante et al., 2021. 3D structure information is as follows: (a) Sweet: 3D molecular representation of the sweet receptor, in purple the TAS1R2 and blue the TAS1R3. The structure consists of the Venus flytrap module (VFTM) with the two lobes (LB1 and LB2), the cysteine-rich domain (CRD) and the transmembrane domain (TMD). (b) Umami: 3D molecular representation of one of the main umami receptor candidates, in green the TAS1R1 and blue the TAS1R3. The structure consists of the Venus flytrap module (VFTM) with the two lobes (LB1 and LB2), the cysteine-rich domain (CRD) and the transmembrane domain (TMD). (c) Bitter: 3D homology model of the TAS2R3 bitter receptor, (d) Salty: Representation of the 3D molecular structure of the trimeric ENaC, (e) Sour: Frontal view of the 3D molecular structure of OTOP1. Each subunit is formed by two structurally homologous domains, i.e. the N domain (light shade) and C domain (dark shade)

Taste is a multifactorial and complex procedure, involving pathways and interactions between a wide range of ligands and proteins. The first step of the taste perception process is the interplay between the chemical components of the food and a specific type of protein intracellular receptors, called taste receptors (taste receptor cells – TRCs). Taste receptors can be found in specialized cells called taste buds, organized in epithelial structures called papillae and can be found in areas like the oral mucosa and the tongue. But taste receptors can be found in other places too, for example in the outermost parts of the digestive system, i.e. larynx and upper esophagus. Sweet receptors (T1R2/T1R3) can, also, be found in the brain, heart, kidney, bladder, nasal respiratory epithelium, gut, pancreas etc., where they play an important metabolic role. What is more, taste receptors do not all belong to the same category. More specifically, sweet and umami taste receptors belong to the G protein-coupled receptors (GPCRs) category, while on the other hand, ion channels mediate sour and salty taste due to the presence of ions. It is, therefore, apparent that there can be a fascinating but complex network of interactions between the many different types of ligands present in the food and the different types of receptors of the human gustatory system.

Sweet and Umami tastes arise through the recognition of ligands from the GPCR type of receptors. To become more definite, sweet taste receptors are a product of the heterodimerization between TAS1R2 and TAS1R3, thus forming a GCPR that belongs to the GCPR- C family. This receptor recognizes natural sugars (e.g. glucose), artificial sweeteners (e.g. aspartame), sweet proteins (e.g. brazzein) and D-amino acids (e.g. D-Phenylalanine).  Umami taste receptors, also arise from the dimerization of two GCPRs, TAS1R1 and TAS1R3, which interact with a wide variety of chemical substances such as amino acids, dipeptide and tripeptides, nucleotide enhancers and organic acids. The TAS1R1-TAS1R3 receptors also belong to the GCPR- C family.

On the other hand, salty and bitter receptors consist of a single type of receptor. Salty taste is mediated through the ENaC receptor, which allows the intracellular passage of Na+ ions. These ions are which, in turn, initiate the perception of saltiness from the gustatory system. The taste receptor type 2 family of GPCRs (TAS2Rs) are the receptors responsible for bitter taste. They belong to the F or A class of GPCRs. Monomeric TAS2Rs (specifically TAS2R10, TAS2R14 and TAS2R46) recognize about one-third of all bitter compounds (such as Diphenidol, Lupolon, Quinine, Benzoin, Arborescin etc.), thus the need for heterodimerization may not be necessary. But in vitro experiments have demonstrated that TAS2Rs are able to form oligomers through homo- and heterodimerization, which may imply that the interactions between TAS2Rs play a role in bitter taste perception (Behrens & Meyerhof, 2018).

Sour taste perception is achieved through the OTOP1 receptor, which is essentially an H+ ion transduction channel. H+ ions are derived from acidic products, such as citric acid, tartaric acid, acetic acid, and hydrochloric acid. Along with other orthologue proteins such as OTOP2, OTOP3, etc., they form the Otopetrins family, but they don’t seem to form multimers or interact with other proteins, in order to facilitate sour perception.

It is apparent, nonetheless, that interactions among taste receptors (by forming homo- and heterodimers) and between taste receptors and other ligands (like peptides), are more than common in order to achieve taste perception, especially in the case of sweet and umami. Consequently, the study of protein-protein interactions in the context of taste receptors may be very beneficial in unravelling new mechanisms of taste perception.

This article was written by Harris Zaverdas, a Data Analyst at InSyBio. In February 2021, he graduated from the Department of Biology of the University of Patras, with a specialization in Genetics, Cell Biology and Developmental Biology. In his Bachelor’s studies, he gained wet lab experience in techniques such as PCR, Elisa, Cell Culturing (especially in neural and neural-stem cells) and more. Since September 2022, he is enrolled in the “Informatics for Life Sciences” MSc program with a specialization in Bioinformatics. During his MSc studies, he has gained skills in Data Analysis, NGS techniques and programming using R, C# and Python. Currently, he is also part of the Virtuous Horizon 2020 funded project (https://virtuoush2020.com), doing his secondment period in Politecnico di Torino.


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