Systematic analysis reveals novel insight into the molecular determinants of function, diversity and evolution of sweet taste receptors T1R2/T1R3 in primates

Abstract

Sweet taste is a primary sensation for the preference and adaption of primates to diet, which is crucial for their survival and fitness. It is clear now that the sweet perception is mediated by a G protein-coupled receptor (GPCR)-sweet taste receptor T1R2/T1R3, and many behavioral or physiological experiments have described the diverse sweet taste sensitivities in primates. However, the structure-function relationship of T1R2s/T1R3s in primates, especially the molecular basis for their species-dependent sweet taste, has not been well understood until now. In this study, we performed a comprehensive sequence, structural and functional analysis of sweet taste receptors in primates to elucidate the molecular determinants mediating their species-dependent sweet taste recognition. Our results reveal distinct taxonomic distribution and significant characteristics (interaction, coevolution and epistasis) of specific key function-related residues, which could partly account for the previously reported behavioral results of taste perception in primates. Moreover, the prosimians Lemuriformes species, which were reported to have no sensitivity to aspartame, could be proposed to be aspartame tasters based on the present analysis. Collectively, our study provides new insights and promotes a better understanding for the diversity, function and evolution of sweet taste receptors in primates.

The Molecular Theory of Sweet Taste: Revisit, Update, and Beyond

“…Since the identification of human sweet taste receptor TAS1R2/TAS1R3 in 2001, substantial research has been steered to interactions between sweeteners and the receptor as well as the activation mechanism of sweet taste receptor. All findings verified the previous assumption that diverse sweeteners act on a common receptor. − Based on its homology to other class C G-protein-coupled receptors (GPCRs) such as metabotropic glutamate receptors (mGluRs), the structure of heterodimeric human TAS1R2/TAS1R3 has been widely acknowledged with each subunit including an extracellular N-terminal Venus flytrap domain (VFD) and a heptahelical transmembrane domain (TMD), which are linked by a cysteine-rich domain (CRD) (Figure b) . Previous studies have shown that many sweeteners enter the pocket located at VFD of TAS1R2 (VFD2) or TAS1R3 (VFD3), while some bind to TMD of TAS1R3 (TMD3). , Sweet taste is initiated by a conformational closure of two lobes of VFD upon sweetener binding, followed by a signal transmission along CRD to TMD, and eventually induced by coupling with G protein and downstream signaling .…”

“…(1) The identified “pincer residues” at the upper lobe (e.g., K65 and R383) and the bottom lobe (e.g., D278 and D307) of VFD2, which is an orthosteric binding region for majority of sweeteners, can be regarded as the interactive counterparts of AH and B glucophores, respectively. There are other potential residues (e.g., E302) with this behavior (Figure c), − as shown in the complementary sweetener–receptor interactions described above. AH and B glucophores of sweeteners interact with these “pincer residues” to induce the conformational closure of two lobes of VFD2 to initiate receptor activation .…”

“…(a) Chemical structures of sweet taste amino acids and their glucophores assignment; (b) chemical structure of aspartame and its glucophores assignment; (c) Phe; (d) Tyr; (e) Trp; (f) Leu; (g) Gly, three-dimensional structures of both d - and l -amino acids are shown and AH, B, and X glucophores of sweet taste d -amino acids are indicated. Hydrogen atoms are omitted; (h) an interaction model between sweet taste amino acids and receptor; (i) two types of conformations of aspartame; (j) the binding site of d -Trp in VFD2 and key residues involved in the amino acid receptor interaction; and (k) the binding site of aspartame in VFD2 . The carbon atoms of d -Trp and aspartame are colored in yellow, and those of their AH, B, and X glucophore interaction residues are colored in orange-red, blue, and green, respectively.…”

“…It should be informative to investigate the detailed atomistic mechanism and key residues involved in the amino acid receptor interaction; 27 and (k) the binding site of aspartame in VFD2. 20 The carbon atoms of D-Trp and aspartame are colored in yellow, and those of their AH, B, and X glucophore interaction residues are colored in orange-red, blue, and green, respectively. Electrostatic interactions between glucophores and receptor residues are denoted as dashed lines.…”

“…The homology model of human TAS1R2/TAS1R3 was constructed with the heterodimeric human metabotropic GABA (γ-aminobutyric acid) (b) receptor (PDB 6UO8) as the template. Sweeteners (e.g., aspartame) were docked into the modeled structure of human TAS1R2/TAS1R3 as described previously, and details of the interaction model between sweeteners and human sweet taste receptor can be found in the “Materials and Methods” of ref . All figures in this article were made with PyMOL software.…”