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APC Inhibits Ligand-Independent Wnt Signaling by the Clathrin Endocytic Pathway.
Saito-Diaz K, Benchabane H, Tiwari A, Tian A, Li B, Thompson JJ, Hyde AS, Sawyer LM, Jodoin JN, Santos E, Lee LA, Coffey RJ, Beauchamp RD, Williams CS, Kenworthy AK, Robbins DJ, Ahmed Y, Lee E
(2018) Dev Cell 44: 566-581.e8
MeSH Terms: Adenomatous Polyposis Coli Protein, Animals, Cells, Cultured, Clathrin, Drosophila melanogaster, Endocytosis, Female, Humans, Infant, Ligands, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Wnt Proteins, Wnt Signaling Pathway, beta Catenin
Show Abstract · Added March 14, 2018
Adenomatous polyposis coli (APC) mutations cause Wnt pathway activation in human cancers. Current models for APC action emphasize its role in promoting β-catenin degradation downstream of Wnt receptors. Unexpectedly, we find that blocking Wnt receptor activity in APC-deficient cells inhibits Wnt signaling independently of Wnt ligand. We also show that inducible loss of APC is rapidly followed by Wnt receptor activation and increased β-catenin levels. In contrast, APC2 loss does not promote receptor activation. We show that APC exists in a complex with clathrin and that Wnt pathway activation in APC-deficient cells requires clathrin-mediated endocytosis. Finally, we demonstrate conservation of this mechanism in Drosophila intestinal stem cells. We propose a model in which APC and APC2 function to promote β-catenin degradation, and APC also acts as a molecular "gatekeeper" to block receptor activation via the clathrin pathway.
Copyright © 2018 Elsevier Inc. All rights reserved.
0 Communities
4 Members
0 Resources
18 MeSH Terms
Salt-bridge modulates differential calcium-mediated ligand binding to integrin α1- and α2-I domains.
Brown KL, Banerjee S, Feigley A, Abe H, Blackwell TS, Pozzi A, Hudson BG, Zent R
(2018) Sci Rep 8: 2916
MeSH Terms: Amino Acid Sequence, Calcium, Hydrogen Bonding, Integrin alpha1, Integrin alpha2, Ligands, Models, Molecular, Protein Binding, Protein Domains, Thermodynamics
Show Abstract · Added March 21, 2018
Integrins are transmembrane cell-extracellular matrix adhesion receptors that impact many cellular functions. A subgroup of integrins contain an inserted (I) domain within the α-subunits (αI) that mediate ligand recognition where function is contingent on binding a divalent cation at the metal ion dependent adhesion site (MIDAS). Ca is reported to promote α1I but inhibit α2I ligand binding. We co-crystallized individual I-domains with MIDAS-bound Ca and report structures at 1.4 and 2.15 Å resolution, respectively. Both structures are in the "closed" ligand binding conformation where Ca induces minimal global structural changes. Comparisons with Mg-bound structures reveal Mg and Ca bind α1I in a manner sufficient to promote ligand binding. In contrast, Ca is displaced in the α2I domain MIDAS by 1.4 Å relative to Mg and unable to directly coordinate all MIDAS residues. We identified an E152-R192 salt bridge hypothesized to limit the flexibility of the α2I MIDAS, thus, reducing Ca binding. A α2I E152A construct resulted in a 10,000-fold increase in Mg and Ca binding affinity while increasing binding to collagen ligands 20%. These data indicate the E152-R192 salt bridge is a key distinction in the molecular mechanism of differential ion binding of these two I domains.
0 Communities
1 Members
0 Resources
10 MeSH Terms
Wnt6 maintains anterior escort cells as an integral component of the germline stem cell niche.
Wang X, Page-McCaw A
(2018) Development 145:
MeSH Terms: Animals, Animals, Genetically Modified, Bone Morphogenetic Proteins, Cadherins, Cell Count, Cell Differentiation, Cell Lineage, Cell Survival, Drosophila Proteins, Drosophila melanogaster, Female, Germ Cells, Ligands, Models, Biological, Ovary, Signal Transduction, Stem Cell Niche, Wnt Proteins
Show Abstract · Added March 20, 2018
Stem cells reside in a niche, a local environment whose cellular and molecular complexity is still being elucidated. In ovaries, germline stem cells depend on cap cells for self-renewing signals and physical attachment. Germline stem cells also contact the anterior escort cells, and here we report that anterior escort cells are absolutely required for germline stem cell maintenance. When escort cells die from impaired Wnt signaling or expression, the loss of anterior escort cells causes loss of germline stem cells. Anterior escort cells function as an integral niche component by promoting DE-cadherin anchorage and by transiently expressing the Dpp ligand to promote full-strength BMP signaling in germline stem cells. Anterior escort cells are maintained by Wnt6 ligands produced by cap cells; without Wnt6 signaling, anterior escort cells die leaving vacancies in the niche, leading to loss of germline stem cells. Our data identify anterior escort cells as constituents of the germline stem cell niche, maintained by a cap cell-produced Wnt6 survival signal.
© 2018. Published by The Company of Biologists Ltd.
0 Communities
1 Members
0 Resources
18 MeSH Terms
The molecular basis of subtype selectivity of human kinin G-protein-coupled receptors.
Joedicke L, Mao J, Kuenze G, Reinhart C, Kalavacherla T, Jonker HRA, Richter C, Schwalbe H, Meiler J, Preu J, Michel H, Glaubitz C
(2018) Nat Chem Biol 14: 284-290
MeSH Terms: Animals, HEK293 Cells, Humans, Insecta, Kinins, Ligands, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Docking Simulation, Mutation, Peptides, Protein Binding, Protein Domains, Protein Structure, Secondary, Receptor, Bradykinin B1, Receptor, Bradykinin B2, Receptors, G-Protein-Coupled, Sf9 Cells, Signal Transduction, Static Electricity
Show Abstract · Added March 17, 2018
G-protein-coupled receptors (GPCRs) are the most important signal transducers in higher eukaryotes. Despite considerable progress, the molecular basis of subtype-specific ligand selectivity, especially for peptide receptors, remains unknown. Here, by integrating DNP-enhanced solid-state NMR spectroscopy with advanced molecular modeling and docking, the mechanism of the subtype selectivity of human bradykinin receptors for their peptide agonists has been resolved. The conserved middle segments of the bound peptides show distinct conformations that result in different presentations of their N and C termini toward their receptors. Analysis of the peptide-receptor interfaces reveals that the charged N-terminal residues of the peptides are mainly selected through electrostatic interactions, whereas the C-terminal segments are recognized via both conformations and interactions. The detailed molecular picture obtained by this approach opens a new gateway for exploring the complex conformational and chemical space of peptides and peptide analogs for designing GPCR subtype-selective biochemical tools and drugs.
0 Communities
1 Members
0 Resources
20 MeSH Terms
Predictive Power of Different Types of Experimental Restraints in Small Molecule Docking: A Review.
Fu DY, Meiler J
(2018) J Chem Inf Model 58: 225-233
MeSH Terms: Algorithms, Drug Design, Drug Discovery, Ligands, Magnetic Resonance Spectroscopy, Molecular Docking Simulation, Proteins, Small Molecule Libraries, Structure-Activity Relationship, User-Computer Interface
Show Abstract · Added March 17, 2018
Incorporating experimental restraints is a powerful method of increasing accuracy in computational protein small molecule docking simulations. Different algorithms integrate distinct forms of biochemical data during the docking and/or scoring stages. These so-called hybrid methods make use of receptor-based information such as nuclear magnetic resonance (NMR) restraints or small molecule-based information such as structure-activity relationships (SARs). A third class of methods directly interrogates contacts between the protein receptor and the small molecule. This work reviews the current state of using such restraints in docking simulations, evaluates their feasibility across broad systems, and identifies potential areas of algorithm development.
0 Communities
1 Members
0 Resources
10 MeSH Terms
Sigma-1 receptor ligands inhibit catecholamine secretion from adrenal chromaffin cells due to block of nicotinic acetylcholine receptors.
Brindley RL, Bauer MB, Hartley ND, Horning KJ, Currie KPM
(2017) J Neurochem 143: 171-182
MeSH Terms: Adrenal Medulla, Animals, Anisoles, Catecholamines, Cattle, Cells, Cultured, Chromaffin Cells, Dose-Response Relationship, Drug, Ligands, Male, Mice, Mice, Inbred C57BL, Nicotinic Antagonists, Propylamines, Receptors, Nicotinic, Receptors, sigma
Show Abstract · Added September 28, 2017
Adrenal chromaffin cells (ACCs) are the neuroendocrine arm of the sympathetic nervous system and key mediators of the physiological stress response. Acetylcholine (ACh) released from preganglionic splanchnic nerves activates nicotinic acetylcholine receptors (nAChRs) on chromaffin cells causing membrane depolarization, opening voltage-gated Ca channels (VGCC), and exocytosis of catecholamines and neuropeptides. The serotonin transporter is expressed in ACCs and interacts with 5-HT receptors to control secretion. In addition to blocking the serotonin transporter, some selective serotonin reuptake inhibitors (SSRIs) are also agonists at sigma-1 receptors which function as intracellular chaperone proteins and can translocate to the plasma membrane to modulate ion channels. Therefore, we investigated whether SSRIs and other sigma-1 receptor ligands can modulate stimulus-secretion coupling in ACCs. Escitalopram and fluvoxamine (100 nM to 1 μM) reversibly inhibited nAChR currents. The sigma-1 receptor antagonists NE-100 and BD-1047 also blocked nAChR currents (≈ 50% block at 100 nM) as did PRE-084, a sigma-1 receptor agonist. Block of nAChR currents by fluvoxamine and NE-100 was not additive suggesting a common site of action. VGCC currents were unaffected by the drugs. Neither the increase in cytosolic [Ca ] nor the resulting catecholamine secretion evoked by direct membrane depolarization to bypass nAChRs was altered by fluvoxamine or NE-100. However, both Ca entry and catecholamine secretion evoked by the cholinergic agonist carbachol were significantly reduced by fluvoxamine or NE-100. Together, our data suggest that sigma-1 receptors do not acutely regulate catecholamine secretion. Rather, SSRIs and other sigma-1 receptor ligands inhibit secretion evoked by cholinergic stimulation because of direct block of Ca entry via nAChRs.
© 2017 International Society for Neurochemistry.
0 Communities
1 Members
0 Resources
16 MeSH Terms
CD318 is a ligand for CD6.
Enyindah-Asonye G, Li Y, Ruth JH, Spassov DS, Hebron KE, Zijlstra A, Moasser MM, Wang B, Singer NG, Cui H, Ohara RA, Rasmussen SM, Fox DA, Lin F
(2017) Proc Natl Acad Sci U S A 114: E6912-E6921
MeSH Terms: A549 Cells, Animals, Antigens, CD, Antigens, Differentiation, T-Lymphocyte, Antigens, Neoplasm, Arthritis, Rheumatoid, Cell Adhesion Molecules, Cell Line, Cell Line, Tumor, Encephalomyelitis, Autoimmune, Experimental, Humans, Ligands, Membrane Glycoproteins, Mice, Inbred C57BL, Mice, Knockout, Neoplasm Proteins, Synovial Membrane, T-Lymphocytes
Show Abstract · Added March 22, 2018
It has been proposed that CD6, an important regulator of T cells, functions by interacting with its currently identified ligand, CD166, but studies performed during the treatment of autoimmune conditions suggest that the CD6-CD166 interaction might not account for important functions of CD6 in autoimmune diseases. The antigen recognized by mAb 3A11 has been proposed as a new CD6 ligand distinct from CD166, yet the identity of it is hitherto unknown. We have identified this CD6 ligand as CD318, a cell surface protein previously found to be present on various epithelial cells and many tumor cells. We found that, like CD6 knockout (KO) mice, CD318 KO mice are also protected in experimental autoimmune encephalomyelitis. In humans, we found that CD318 is highly expressed in synovial tissues and participates in CD6-dependent adhesion of T cells to synovial fibroblasts. In addition, soluble CD318 is chemoattractive to T cells and levels of soluble CD318 are selectively and significantly elevated in the synovial fluid from patients with rheumatoid arthritis and juvenile inflammatory arthritis. These results establish CD318 as a ligand of CD6 and a potential target for the diagnosis and treatment of autoimmune diseases such as multiple sclerosis and inflammatory arthritis.
0 Communities
1 Members
0 Resources
18 MeSH Terms
Kinetic processivity of the two-step oxidations of progesterone and pregnenolone to androgens by human cytochrome P450 17A1.
Gonzalez E, Guengerich FP
(2017) J Biol Chem 292: 13168-13185
MeSH Terms: 17-alpha-Hydroxypregnenolone, Androstenedione, Animals, Binding Sites, Biocatalysis, Cytochrome P-450 Enzyme Inhibitors, Cytochromes b5, Dehydroepiandrosterone, Humans, Imidazoles, Kinetics, Ligands, Models, Molecular, NADPH-Ferrihemoprotein Reductase, Naphthalenes, Oxidation-Reduction, Pregnenolone, Progesterone, Protein Conformation, Rats, Recombinant Proteins, Stereoisomerism, Steroid 17-alpha-Hydroxylase
Show Abstract · Added March 14, 2018
Cytochrome P450 (P450, CYP) 17A1 plays a critical role in steroid metabolism, catalyzing both the 17α-hydroxylation of pregnenolone and progesterone and the subsequent 17α,20-lyase reactions to form dehydroepiandrosterone (DHEA) and androstenedione (Andro), respectively, critical for generating glucocorticoids and androgens. Human P450 17A1 reaction rates examined are enhanced by the accessory protein cytochrome (), but the exact role of in P450 17A1-catalyzed reactions is unclear as are several details of these reactions. Here, we examined in detail the processivity of the 17α-hydroxylation and lyase steps. did not enhance reaction rates by decreasing the rates of any of the steroids. Steroid binding to P450 17A1 was more complex than a simple two-state system. Pre-steady-state experiments indicated lag phases for Andro production from progesterone and for DHEA from pregnenolone, indicating a distributive character of the enzyme. However, we observed processivity in pregnenolone/DHEA pulse-chase experiments. ()-Orteronel was three times more inhibitory toward the conversion of 17α-hydroxypregnenolone to DHEA than toward the 17α-hydroxylation of pregnenolone. IC values for ()-orteronel were identical for blocking DHEA formation from pregnenolone and for 17α-hydroxylation, suggestive of processivity. Global kinetic modeling helped assign sets of rate constants for individual or groups of reactions, indicating that human P450 17A1 is an inherently distributive enzyme but that some processivity is present, some of the 17α-OH pregnenolone formed from pregnenolone did not dissociate from P450 17A1 before conversion to DHEA. Our results also suggest multiple conformations of P450 17A1, as previously proposed on the basis of NMR spectroscopy and X-ray crystallography.
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
0 Communities
1 Members
0 Resources
23 MeSH Terms
cytochrome P450 46A1 (CYP46A1) activation by neuroactive compounds.
Mast N, Anderson KW, Johnson KM, Phan TTN, Guengerich FP, Pikuleva IA
(2017) J Biol Chem 292: 12934-12946
MeSH Terms: Acetylcholine, Allosteric Regulation, Amino Acid Substitution, Anti-HIV Agents, Aspartic Acid, Benzoxazines, Binding Sites, Biocatalysis, Cholesterol 24-Hydroxylase, Deuterium Exchange Measurement, Enzyme Activation, Glutamic Acid, Ligands, Models, Molecular, Molecular Docking Simulation, Mutagenesis, Site-Directed, Mutation, Nerve Tissue Proteins, Peptide Fragments, Protein Conformation, Recombinant Fusion Proteins, gamma-Aminobutyric Acid
Show Abstract · Added March 14, 2018
Cytochrome P450 46A1 (CYP46A1, cholesterol 24-hydroxylase) is the enzyme responsible for the majority of cholesterol elimination from the brain. Previously, we found that the anti-HIV drug efavirenz (EFV) can pharmacologically activate CYP46A1 in mice. Herein, we investigated whether CYP46A1 could also be activated by endogenous compounds, including major neurotransmitters. experiments with purified recombinant CYP46A1 indicated that CYP46A1 is activated by l-glutamate (l-Glu), l-aspartate, γ-aminobutyric acid, and acetylcholine, with l-Glu eliciting the highest increase (3-fold) in CYP46A1-mediated cholesterol 24-hydroxylation. We also found that l-Glu and other activating neurotransmitters bind to the same site on the CYP46A1 surface, which differs from the EFV-binding site. The other principal differences between EFV and l-Glu in CYP46A1 activation include an apparent lack of l-Glu binding to the P450 active site and different pathways of signal transduction from the allosteric site to the active site. EFV and l-Glu similarly increased the CYP46A1 , the rate of the "fast" phase of the enzyme reduction by the redox partner NADPH-cytochrome P450 oxidoreductase, and the amount of P450 reduced. Spectral titrations with cholesterol, in the presence of EFV or l-Glu, suggest that water displacement from the heme iron can be affected in activator-bound CYP46A1. Moreover, EFV and l-Glu synergistically activated CYP46A1. Collectively, our data, along with those from previous cell culture and studies by others, suggest that l-Glu-induced CYP46A1 activation is of physiological relevance.
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
0 Communities
1 Members
0 Resources
22 MeSH Terms
Prostaglandin E glyceryl ester is an endogenous agonist of the nucleotide receptor P2Y.
Brüser A, Zimmermann A, Crews BC, Sliwoski G, Meiler J, König GM, Kostenis E, Lede V, Marnett LJ, Schöneberg T
(2017) Sci Rep 7: 2380
MeSH Terms: Animals, Binding Sites, Cell Line, Tumor, Cyclooxygenase 2, Dinoprostone, HEK293 Cells, High-Throughput Nucleotide Sequencing, High-Throughput Screening Assays, Humans, Kinetics, Ligands, Mice, Molecular Docking Simulation, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, Purinergic Agonists, RAW 264.7 Cells, Receptors, Purinergic P2, Substrate Specificity, Thermodynamics, Transcriptome
Show Abstract · Added March 17, 2018
Cyclooxygenase-2 catalyses the biosynthesis of prostaglandins from arachidonic acid but also the biosynthesis of prostaglandin glycerol esters (PG-Gs) from 2-arachidonoylglycerol. Previous studies identified PG-Gs as signalling molecules involved in inflammation. Thus, the glyceryl ester of prostaglandin E, PGE-G, mobilizes Ca and activates protein kinase C and ERK, suggesting the involvement of a G protein-coupled receptor (GPCR). To identify the endogenous receptor for PGE-G, we performed a subtractive screening approach where mRNA from PGE-G response-positive and -negative cell lines was subjected to transcriptome-wide RNA sequencing analysis. We found several GPCRs that are only expressed in the PGE-G responder cell lines. Using a set of functional readouts in heterologous and endogenous expression systems, we identified the UDP receptor P2Y as the specific target of PGE-G. We show that PGE-G and UDP are both agonists at P2Y, but they activate the receptor with extremely different EC values of ~1 pM and ~50 nM, respectively. The identification of the PGE-G/P2Y pair uncovers the signalling mode of PG-Gs as previously under-appreciated products of cyclooxygenase-2.
0 Communities
2 Members
0 Resources
23 MeSH Terms