Structure basis for sugar specificity of gustatory receptors in insects.
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ABSTRACT:
SUBMITTER: Chen R
PROVIDER: S-EPMC11300463 | biostudies-literature | 2024 Aug
REPOSITORIES: biostudies-literature
Publications
Structure basis for sugar specificity of gustatory receptors in insects.
Chen Ruizhu R Zhang Ran R Li Lu L Wang Bozhan B Gao Zhiwei Z Liu Fenglian F Chen Yan Y Tian Yutao Y Li Baobin B Chen Qingfeng Q
Cell discovery 20240806 1
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Project description:BackgroundPerception of sugars is an invaluable ability for insects which often derive quickly accessible energy from these molecules. A distinctive subfamily of eight proteins within the gustatory receptor (Gr) family has been identified as sugar receptors (SRs) in Drosophila melanogaster (Gr5a, Gr61a, and Gr64a-f). We examined the evolution of these SRs within the 12 available Drosophila genome sequences, as well as three mosquito, two moth, and beetle, bee, and wasp genome sequences.ResultsWhile most Drosophila species retain all eight genes, we find that the three Drosophila subgenus species have lost Gr64d, while D. grimshawi and the D. pseudoobscura/persimilis sibling species have also lost Gr5a function. The entire Gr64 gene complex was also duplicated in the D. grimshawi lineage, but only one potentially functional copy of each gene has been retained. The numbers of SRs range from two in the hymenopterans Apis mellifera and Nasonia vitripennis to 16 in the beetle Tribolium castaneum. An unusual aspect is the evolution of a novel exon from intronic sequence in an expanded set of four SRs in Bombyx mori (BmGr5-8), which appears to be the first example of such exonization in insects. Twelve intron gains and 63 losses are inferred within the SR family.ConclusionExamination of the SRs in these fly, mosquito, moth, beetle, and hymenopteran genome sequences reveals that they appear to have originated independently from single ancestral genes within the dipteran and coleopteran lineages, and two genes in the lepidopteran and hymenopteran lineages. The origin of the insect SRs will eventually be illuminated by additional basal insect and arthropod genome sequences.
| S-EPMC2667405 | biostudies-literature
Project description:The mechanisms by which the fruit fly Drosophila melanogaster detects sweet compounds are poorly understood; however, a subset of the family of 68 gustatory receptors (Grs) has emerged as the key receptors. These seven transmembrane receptors include Gr5a and at least one member of the six genes in the Gr64 cluster (Gr64a), which are expressed in sugar-responsive neurons. Disruption of Gr5a prevents the detection of trehalose [1-3], whereas mutation of Gr64a impairs the responses to sucrose, maltose, and glucose [4, 5]. Recent studies suggest that these sugar receptors may require a coreceptor for function in vivo [4-6]; however, the identity of the putative coreceptor is not known. In the current work, we demonstrate that Gr64f is required in combination with Gr5a for the behavioral response to trehalose and for production of nerve responses to trehalose. Gr64f was also required in concert with Gr64a to rescue the defects in the sensitivities to sucrose, maltose, and glucose, resulting from deletion of the entire Gr64 cluster. These data suggest that Drosophila sugar receptors function as multimers and that Gr64f is required broadly as a coreceptor for the detection of sugars.
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Project description:Nucleotide sugar (NS) dehydratases play a central role in the biosynthesis of deoxy and amino sugars, which are involved in a variety of biological functions in all domains of life. Bacteria are true masters of deoxy sugar biosynthesis as they can produce a wide range of highly specialized monosaccharides. Indeed, deoxy and amino sugars play important roles in the virulence of gram-positive and gram-negative pathogenic species and are additionally involved in the biosynthesis of diverse macrolide antibiotics. The biosynthesis of deoxy sugars relies on the activity of NS dehydratases, which can be subdivided into three groups based on their structure and reaction mechanism. The best-characterized NS dehydratases are the 4,6-dehydratases that, together with the 5,6-dehydratases, belong to the NS-short-chain dehydrogenase/reductase superfamily. The other two groups are the less abundant 2,3-dehydratases that belong to the Nudix hydrolase superfamily and 3-dehydratases, which are related to aspartame aminotransferases. 4,6-Dehydratases catalyze the first step in all deoxy sugar biosynthesis pathways, converting nucleoside diphosphate hexoses to nucleoside diphosphate-4-keto-6-deoxy hexoses, which in turn are further deoxygenated by the 2,3- and 3-dehydratases to form dideoxy and trideoxy sugars. In this review, we give an overview of the NS dehydratases focusing on the comparison of their structure and reaction mechanisms, thereby highlighting common features, and investigating differences between closely related members of the same superfamilies.
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Project description:DEET is the most widely used insect repellent worldwide. In Drosophila olfactory receptor neurons (ORNs), DEET is detected through a mechanism employing the olfactory receptor, OR83b. However, it is controversial as to whether ORNs respond directly to DEET or whether DEET blocks the response to attractive odors. Here, we showed that DEET suppressed feeding behavior in Drosophila, and this effect was mediated by gustatory receptor neurons (GRNs). DEET was potent in suppressing feeding as <0.1% DEET elicited aversive behavior. Inhibition of feeding required multiple gustatory receptors (GRs) expressed in inhibitory GRNs. DEET stimulated action potentials in GRNs that respond to aversive compounds, and this response was lost in the Gr32a, Gr33a, and Gr66a mutants. Since 0.02% DEET elicited action potentials, we conclude that DEET directly activates of GRNs. We suggest that the effectiveness of DEET in pest control owes to its dual action in inducing avoidance simultaneously via GRNs and ORNs.
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Project description:In stereotyped neuronal networks, synaptic connectivity is dictated by cell surface proteins, which assign unique identities to neurons, and physically mediate axon guidance and synapse targeting. We recently identified two groups of immunoglobulin superfamily proteins in Drosophila, Dprs and DIPs, as strong candidates for synapse targeting functions. Here, we uncover the molecular basis of specificity in Dpr-DIP mediated cellular adhesions and neuronal connectivity. First, we present five crystal structures of Dpr-DIP and DIP-DIP complexes, highlighting the evolutionary and structural origins of diversification in Dpr and DIP proteins and their interactions. We further show that structures can be used to rationally engineer receptors with novel specificities or modified affinities, which can be used to study specific circuits that require Dpr-DIP interactions to help establish connectivity. We investigate one pair, engineered Dpr10 and DIP-α, for function in the neuromuscular circuit in flies, and reveal roles for homophilic and heterophilic binding in wiring.
| S-EPMC6374074 | biostudies-literature
Project description:Insects sense the taste of foods and toxic compounds in their environment through the gustatory system. Genetic studies using fruit flies have suggested that putative seven-transmembrane gustatory receptors (Grs) expressed in gustatory sensory neurons are required for responses to specific tastants. We reconstituted sugar responses of Bombyx mori Gr-9 (BmGr-9), a silkworm Gr, in two heterologous expression systems. Xenopus oocytes or HEK293T cells expressing BmGr-9 selectively responded to D-fructose with an influx of extracellular Ca(2+) and a nonselective cation current conductance in a G protein-independent manner. Outside-out patch-clamp recording of BmGr-9-expressing cell membranes provides evidence supporting the hypothesis that BmGr-9 constitutes a ligand-gated ion channel. The fructose-activated current associated with BmGr-9 was suppressed by other hexoses, including glucose and sorbose. The activation and inhibition of insect Gr ion channels may be the molecular basis for the decoding system that discriminates subtle differences in sweet taste. Finally, Drosophila melanogaster Gr43a (DmGr43a), a BmGr-9 ortholog, also responded to D-fructose, suggesting that DmGr43a relatives appear to compose the family of fructose receptors.
| S-EPMC3136286 | biostudies-literature
Project description:Nucleotide sugars are the activated form of monosaccharides used by glycosyltransferases during glycosylation. In eukaryotes the SLC35 family of solute carriers are responsible for their selective uptake into the Endoplasmic Reticulum or Golgi apparatus. The structure of the yeast GDP-mannose transporter, Vrg4, revealed a requirement for short chain lipids and a marked difference in transport rate between the nucleotide sugar and nucleoside monophosphate, suggesting a complex network of regulatory elements control transport into these organelles. Here we report the crystal structure of the GMP bound complex of Vrg4, revealing the molecular basis for GMP recognition and transport. Molecular dynamics, combined with biochemical analysis, reveal a lipid mediated dimer interface and mechanism for coordinating structural rearrangements during transport. Together these results provide further insight into how SLC35 family transporters function within the secretory pathway and sheds light onto the role that membrane lipids play in regulating transport across the membrane.
| S-EPMC6789118 | biostudies-literature
Project description:In the fruit fly Drosophila melanogaster, gustatory sensory neurons express taste receptors that are tuned to distinct groups of chemicals, thereby activating neural ensembles that elicit either feeding or avoidance behavior. Members of a family of ligand -gated receptor channels, the Gustatory receptors (Grs), play a central role in these behaviors. In general, closely related, evolutionarily conserved Gr proteins are co-expressed in the same type of taste neurons, tuned to chemically related compounds, and therefore triggering the same behavioral response. Here, we report that members of the Gr28 subfamily are expressed in largely non-overlapping sets of taste neurons in Drosophila larvae, detect chemicals of different valence, and trigger opposing feeding behaviors. We determined the intrinsic properties of Gr28 neurons by expressing the mammalian Vanilloid Receptor 1 (VR1), which is activated by capsaicin, a chemical to which wild-type Drosophila larvae do not respond. When VR1 is expressed in Gr28a neurons, larvae become attracted to capsaicin, consistent with reports showing that Gr28a itself encodes a receptor for nutritious RNA. In contrast, expression of VR1 in two pairs of Gr28b.c neurons triggers avoidance to capsaicin. Moreover, neuronal inactivation experiments show that the Gr28b.c neurons are necessary for avoidance of several bitter compounds. Lastly, behavioral experiments of Gr28 deficient larvae and live Ca2+ imaging studies of Gr28b.c neurons revealed that denatonium benzoate, a synthetic bitter compound that shares structural similarities with natural bitter chemicals, is a ligand for a receptor complex containing a Gr28b.c or Gr28b.a subunit. Thus, the Gr28 proteins, which have been evolutionarily conserved over 260 million years in insects, represent the first taste receptor subfamily in which specific members mediate behavior with opposite valence.
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Project description:Binding specificity between fibroblast growth factors (FGFs) and their receptors (FGFRs) is essential for mammalian development and is regulated primarily by two alternatively spliced exons, IIIb ("b") and IIIc ("c"), that encode the second half of Ig-like domain 3 (D3) of FGFRs. FGF7 and FGF10 activate only the b isoform of FGFR2 (FGFR2b). Here, we report the crystal structure of the ligand-binding portion of FGFR2b bound to FGF10. Unique contacts between divergent regions in FGF10 and two b-specific loops in D3 reveal the structural basis by which alternative splicing provides FGF10-FGFR2b specificity. Structure-based mutagenesis of FGF10 confirms the importance of the observed contacts for FGF10 biological activity. Interestingly, FGF10 binding induces a previously unobserved rotation of receptor Ig domain 2 (D2) to introduce specific contacts with FGF10. Hence, both D2 and D3 of FGFR2b contribute to the exceptional specificity between FGF10 and FGFR2b. We propose that ligand-induced conformational change in FGFRs may also play an important role in determining specificity for other FGF-FGFR complexes.
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Project description:Sugar moieties in natural products are frequently modified by O-methylation. In the biosynthesis of the macrolide antibiotic mycinamicin, methylation of a 6'-deoxyallose substituent occurs in a stepwise manner first at the 2'- and then the 3'-hydroxyl groups to produce the mycinose moiety in the final product. The timing and placement of the O-methylations impact final stage C-H functionalization reactions mediated by the P450 monooxygenase MycG. The structural basis of pathway ordering and substrate specificity is unknown. A series of crystal structures of MycF, the 3'-O-methyltransferase, including the free enzyme and complexes with S-adenosyl homocysteine (SAH), substrate, product, and unnatural substrates, show that SAM binding induces substantial ordering that creates the binding site for the natural substrate, and a bound metal ion positions the substrate for catalysis. A single amino acid substitution relaxed the 2'-methoxy specificity but retained regiospecificity. The engineered variant produced a new mycinamicin analog, demonstrating the utility of structural information to facilitate bioengineering approaches for the chemoenzymatic synthesis of complex small molecules containing modified sugars. Using the MycF substrate complex and the modeled substrate complex of a 4'-specific homologue, active site residues were identified that correlate with the 3' or 4' specificity of MycF family members and define the protein and substrate features that direct the regiochemistry of methyltransfer. This classification scheme will be useful in the annotation of new secondary metabolite pathways that utilize this family of enzymes.
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