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262 results on '"Forrest, Lucy R."'

1. Intestinal serotonin and fluoxetine exposure modulate bacterial colonization in the gut

Author

Fung, Thomas C, Vuong, Helen E, Luna, Cristopher DG, Pronovost, Geoffrey N, Aleksandrova, Antoniya A, Riley, Noah G, Vavilina, Anastasia, McGinn, Julianne, Rendon, Tomiko, Forrest, Lucy R, and Hsiao, Elaine Y

Subjects
Microbiology, Biological Sciences, Genetics, Prevention, Depression, Digestive Diseases, Nutrition, Mental Health, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Underpinning research, Aetiology, Oral and gastrointestinal, Infection, Administration, Oral, Animals, Bacteria, Feces, Female, Firmicutes, Fluoxetine, Gastrointestinal Microbiome, Genetic Variation, Host Microbial Interactions, Intestines, Male, Mice, Mice, Inbred C57BL, Serotonin, Serotonin Receptor Agonists, Selective Serotonin Reuptake Inhibitors, Specific Pathogen-Free Organisms, Medical Microbiology
Abstract

The gut microbiota regulates levels of serotonin (5-hydroxytryptamine (5-HT)) in the intestinal epithelium and lumen1-5. However, whether 5-HT plays a functional role in bacteria from the gut microbiota remains unknown. We demonstrate that elevating levels of intestinal lumenal 5-HT by oral supplementation or genetic deficiency in the host 5-HT transporter (SERT) increases the relative abundance of spore-forming members of the gut microbiota, which were previously reported to promote host 5-HT biosynthesis. Within this microbial community, we identify Turicibacter sanguinis as a gut bacterium that expresses a neurotransmitter sodium symporter-related protein with sequence and structural homology to mammalian SERT. T. sanguinis imports 5-HT through a mechanism that is inhibited by the selective 5-HT reuptake inhibitor fluoxetine. 5-HT reduces the expression of sporulation factors and membrane transporters in T. sanguinis, which is reversed by fluoxetine exposure. Treating T. sanguinis with 5-HT or fluoxetine modulates its competitive colonization in the gastrointestinal tract of antibiotic-treated mice. In addition, fluoxetine reduces the membership of T. sanguinis in the gut microbiota of conventionally colonized mice. Host association with T. sanguinis alters intestinal expression of multiple gene pathways, including those important for lipid and steroid metabolism, with corresponding reductions in host systemic triglyceride levels and inguinal adipocyte size. Together, these findings support the notion that select bacteria indigenous to the gut microbiota signal bidirectionally with the host serotonergic system to promote their fitness in the intestine.

Published
2019

25. Interpretation of spectroscopic data using molecular simulations for the secondary active transporter BetP

Author

Robertson, Janice, Leone, Vanessa, Waclawska-Krzeminski, Izabela Jadwiga, Kossmann, Katharina, Koshy, Caroline, Sharma, Monika, Prisner, Thomas F., Ziegler, Christine, Endeward, Burkhard, Forrest, Lucy R., Robertson, Janice, Leone, Vanessa, Waclawska-Krzeminski, Izabela Jadwiga, Kossmann, Katharina, Koshy, Caroline, Sharma, Monika, Prisner, Thomas F., Ziegler, Christine, Endeward, Burkhard, and Forrest, Lucy R.

Abstract

Mechanistic understanding of dynamic membrane proteins such as transporters, receptors, and channels requires accurate depictions of conformational ensembles, and the manner in which they interchange as a function of environmental factors including substrates, lipids, and inhibitors. Spectroscopic techniques such as electron spin resonance (ESR) pulsed electron–electron double resonance (PELDOR), also known as double electron–electron resonance (DEER), provide a complement to atomistic structures obtained from x-ray crystallography or cryo-EM, since spectroscopic data reflect an ensemble and can be measured in more native solvents, unperturbed by a crystal lattice. However, attempts to interpret DEER data are frequently stymied by discrepancies with the structural data, which may arise due to differences in conditions, the dynamics of the protein, or the flexibility of the attached paramagnetic spin labels. Recently, molecular simulation techniques such as EBMetaD have been developed that create a conformational ensemble matching an experimental distance distribution while applying the minimal possible bias. Moreover, it has been proposed that the work required during an EBMetaD simulation to match an experimentally determined distribution could be used as a metric with which to assign conformational states to a given measurement. Here, we demonstrate the application of this concept for a sodium-coupled transport protein, BetP. Because the probe, protein, and lipid bilayer are all represented in atomic detail, the different contributions to the work, such as the extent of protein backbone movements, can be separated. This work therefore illustrates how ranking simulations based on EBMetaD can help to bridge the gap between structural and biophysical data and thereby enhance our understanding of membrane protein conformational mechanisms.

Published
2020

35. EncoMPASS: an Encyclopedia of Membrane Proteins Analyzed by Structure and Symmetry

Author

Aleksandrova, Antoniya A., Sarti, Edoardo, and Forrest, Lucy R.

Subjects
Protein structure, Membrane, biology, Membrane protein, Computer science, biology.protein, Encyclopedia, Structure (category theory), Active site, Sequence (biology), Computational biology, Symmetry (geometry), Integral membrane protein
Abstract

SummaryProtein structure determination and prediction, active site detection, and protein sequence alignment techniques all exploit information about protein structure and structural relationships. For membrane proteins, however, there is no agreement among available online tools for highlighting and mapping such structural similarities. Moreover, no available resource provides a systematic overview of quaternary and internal symmetries, and their orientation with respect to the membrane, despite the fact that these properties can provide key insights into membrane protein function. To address these issues, we created theEncyclopediaofMembraneProteinsAnalyzed byStructure and Symmetry (EncoMPASS), a database for relating integral membrane proteins of known structure from the points of view of sequence, structure, and symmetry. EncoMPASS is accessible athttps://encompass.ninds.nih.govand its contents can be easily downloaded. This allows the user not only to focus on specific systems, but also to study general properties of the structure and evolution of membrane proteins.Highlights-EncoMPASS relates and analyzes known structures of membrane proteins-Structure and sequence similarity is assessed through alignments and topology considerations, not clustering-Symmetry is detected based on CE-Symm and SymD using a multi-step procedure

Published
2018

36. RNA Granules Hitchhike on Lysosomes for Long-Distance Transport, Using Annexin A11 as a Molecular Tether

Author

Liao, Ya-Cheng, primary, Fernandopulle, Michael S., additional, Wang, Guozhen, additional, Choi, Heejun, additional, Hao, Ling, additional, Drerup, Catherine M., additional, Patel, Rajan, additional, Qamar, Seema, additional, Nixon-Abell, Jonathon, additional, Shen, Yi, additional, Meadows, William, additional, Vendruscolo, Michele, additional, Knowles, Tuomas P.J., additional, Nelson, Matthew, additional, Czekalska, Magdalena A., additional, Musteikyte, Greta, additional, Gachechiladze, Mariam A., additional, Stephens, Christina A., additional, Pasolli, H. Amalia, additional, Forrest, Lucy R., additional, St George-Hyslop, Peter, additional, Lippincott-Schwartz, Jennifer, additional, and Ward, Michael E., additional

Published
2019
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40. Chloride-dependent conformational changes in the GlyT1 glycine transporter.

Author

Yuan-Wei Zhang, Uchendu, Stacy, Leone, Vanessa, Bradshaw, Richard T., Sangwa, Ntumba, Forrest, Lucy R., and Rudnick, Gary

Subjects
GLYCINE, MOLECULAR dynamics, ION pairs, GLUTAMINE
Abstract

The human GlyT1 glycine transporter requires chloride for its function. However, the mechanism by which Cl-exerts its influence is unknown. To examine the role that Cl-plays in the transport cycle, we measured the effect of Cl-on both glycine binding and conformational changes. The ability of glycine to displace the high-affinity radioligand [3H]CHIBA-3007 required Na+ and was potentiated over 1,000-fold by Cl-. We generated GlyT1b mutants containing reactive cysteine residues in either the extracellular or cytoplasmic permeation pathways and measured changes in the reactivity of those cysteine residues as indicators of conformational changes in response to ions and substrate. Na+ increased accessibility in the extracellular pathway and decreased it in the cytoplasmic pathway, consistent with stabilizing an outward-open conformation as observed in other members of this transporter family. In the presence of Na+, both glycine and Cl-independently shifted the conformation of GlyT1b toward an outward-closed conformation. Together, Na+, glycine, and Cl-stabilized an inward-open conformation of GlyT1b. We then examined whether Cl-acts by interacting with a conserved glutamine to allow formation of an ion pair that stabilizes the closed state of the extracellular pathway. Molecular dynamics simulations of a GlyT1 homolog indicated that this ion pair is formed more frequently as that pathway closes. Mutation of the glutamine blocked the effect of Cl-, and substituting it with glutamate or lysine resulted in outward- or inward-facing transporter conformations, respectively. These results provide an unexpected insight into the role of Cl-in this family of transporters. [ABSTRACT FROM AUTHOR]

Published
2021
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41. Structure and Regulatory Interactions of the Cytoplasmic Terminal Domains of Serotonin Transporter

Author

Fenollar-Ferrer, Cristina, Stockner, Thomas, Schwarz, Thomas C., Pal, Aritra, Gotovina, Jelena, Hofmaier, Tina, Jayaraman, Kumaresan, Adhikary, Suraj, Kudlacek, Oliver, Mehdipour, Ahmadreza, Tavoulari, Sotiria, Rudnick, Gary, Singh, Satinder K., Konrat, Robert, Sitte, Harald H., and Forrest, Lucy R.

Subjects
Models, Molecular, Serotonin Plasma Membrane Transport Proteins, Cytoplasm, Protein Folding, Magnetic Resonance Spectroscopy, Protein Conformation, Circular Dichroism, Molecular Sequence Data, Article, Protein Structure, Secondary, Protein Structure, Tertiary, ddc:570, Fluorescence Resonance Energy Transfer, Humans, Amino Acid Sequence
Abstract

Uptake of neurotransmitters by sodium-coupled monoamine transporters of the NSS family is required for termination of synaptic transmission. Transport is tightly regulated by protein-protein interactions involving the small cytoplasmic segments at the amino- and carboxy-terminal ends of the transporter. Although structures of homologues provide information about the transmembrane regions of these transporters, the structural arrangement of the terminal domains remains largely unknown. Here, we combined molecular modeling, biochemical, and biophysical approaches in an iterative manner to investigate the structure of the 82-residue N-terminal and 30-residue C-terminal domains of human serotonin transporter (SERT). Several secondary structures were predicted in these domains, and structural models were built using the Rosetta fragment-based methodology. One-dimensional (1)H nuclear magnetic resonance and circular dichroism spectroscopy supported the presence of helical elements in the isolated SERT N-terminal domain. Moreover, introducing helix-breaking residues within those elements altered the fluorescence resonance energy transfer signal between terminal cyan fluorescent protein and yellow fluorescent protein tags attached to full-length SERT, consistent with the notion that the fold of the terminal domains is relatively well-defined. Full-length models of SERT that are consistent with these and published experimental data were generated. The resultant models predict confined loci for the terminal domains and predict that they move apart during the transport-related conformational cycle, as predicted by structures of homologues and by the "rocking bundle" hypothesis, which is consistent with spectroscopic measurements. The models also suggest the nature of binding to regulatory interaction partners. This study provides a structural context for functional and regulatory mechanisms involving SERT terminal domains.

Published
2014

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