Progress in solving the structure of insulin bound to its receptor has been slow and stepwise, but a milestone has now been reached with a refined structure of a complex of insulin with a “microreceptor” that contains the primary binding site. The insulin receptor is a dimeric allosteric enzyme that belongs to the family of receptor tyrosine kinases. The insulin binding process is complex and exhibits negative cooperativity. Biochemical evidence suggested that insulin, through two distinct binding sites, (...) crosslinks two receptor sites located on each α subunit. The structure of the unliganded receptor ectodomain showed a symmetrical folded‐over conformation with an antiparallel disposition. Further work resolved the detailed structure of receptor site 1, both without and with insulin. Recently, a missing piece in the puzzle was added: the C‐terminal portion of insulin's B‐chain known to be critical for binding and negative cooperativity. Here I discuss these findings and their implications. (shrink)

Disturbances of consciousness, including fluctuations in attention and awareness, are a common and clinically important symptom in dementia with Lewy bodies. In the present study we investigate potential mechanisms of such disturbances of consciousness in a clinicopathological study evaluating specific components of the cholinergic system. [3H]Epibatidine binding to the high-affinity nicotinic receptor in the temporal cortex differentiated DLB cases with and without DOC, being 62–66% higher in those with DOC. The were no differences between DLB patients with or without (...) DOC in 125I-labeled α-bungaratoxin binding to the low-affinity nicotinic receptor, [3H]pirenzepine binding to the muscarinic M1 receptor, or in choline acetyltransferase activity. These findings provide support for the hypothesis that cholinergic activity is an important neural correlate if consciousness and suggest a mechanism of DOC in DLB involving alterations in the nicotinic receptor, composed of predominantly α4 and β2 subunits. (shrink)

Insulin is a member of a family of hormones, growth factors and neuropeptides which are found in both vertebrates and invertebrates. A common ‘insulin fold’ is probably adopted by all family members. Although the specificities of receptor binding are different, there is possibility of co‐evolution of polypeptides and their receptors.

Stiff Person Syndrome is a rare autoimmune disorder associated with antibodies against glutamic acid decarboxylase, the key enzyme in γ -aminobutyric acid synthesis. In order to investigate the role of cerebral benzodiazepinereceptor binding in SPS, we performed [ 11 C]flumazenil positron emission tomography in a female patient with SPS compared to nine healthy controls. FMZ is a radioligand to the postsynaptic central benzodiazepine receptor which is co-localized with the GABA-A receptor. In the SPS patient, we found a global reduction (...) of cortical FMZ binding. In addition, distinct local clusters of reduced radiotracer binding were observed. These data provide first in vivo evidence for a reduced postsynaptic GABA-A receptor availability which may reflect the loss of GABAergic neuronal inhibition in SPS. (shrink)

Unraveling the molecular detail of insulin receptor activation has proved challenging, but a major advance is the recent determination of crystallographic structures of insulin in complex with its primary binding site on the receptor. The current model for insulin receptor activation is that two distinct surfaces of insulin monomer engage sequentially with two distinct binding sites on the extracellular surface of the insulin receptor, which is itself a disulfide‐linked (αβ)2 homodimer. In the process, conformational changes occur both within (...) the hormone and the receptor, the latter resulting in the disruption of the intracellular interactions that hold the kinase domains in their basal state and in the initiation of the phosphorylation events that drive insulin signaling. The purpose of this paper is to summarize the extant structural data relating to hormone binding and how it effects receptor activation, as well as to discuss the issues that remain unresolved. (shrink)

We propose a biochemical mechanism for celiac disease and non‐celiac gluten sensitivity that may rationalize many of the extradigestive disorders not explained by the current immunogenetic model. Our hypothesis is based on the homology between the 33‐mer gliadin peptide and a component of the NMDA glutamate receptor ion channel – the human GRINA protein – using BLASTP software. Based on this homology the 33‐mer may act as a natural antagonist interfering with the normal interactions of GRINA and its partners. The (...) theory is supported by numerous independent data from the literature, and provides a mechanistic link with otherwise unrelated disorders, such as cleft lip and palate, thyroid dysfunction, restless legs syndrome, depression, ataxia, hearing loss, fibromyalgia, dermatitis herpetiformis, schizophrenia, toxoplasmosis, anemia, osteopenia, Fabry disease, Barret's adenocarcinoma, neuroblastoma, urinary incontinence, recurrent miscarriage, cardiac anomalies, reduced risk of breast cancer, stiff person syndrome, etc. The hypothesis also anticipates better animal models, and has the potential to open new avenues of research. (shrink)

Molecular vibrations and quantum tunneling may link ligand binding to the function of pharmacological receptors. The well‐established lock‐and‐key model explains a ligand's binding and recognition by a receptor; however, a general mechanism by which receptors translate binding into activation, inactivation, or modulation remains elusive. The Vibration Theory of Olfaction was proposed in the 1930s to explain this subset of receptor‐mediated phenomena by correlating odorant molecular vibrations to smell, but a mechanism was lacking. In the 1990s, inelastic electron (...) tunneling was proposed as a plausible mechanism for translating molecular vibration to odorant physiology. More recently, studies of ligands’ vibrational spectra and the use of deuterated ligand analogs have provided helpful information to study this admittedly controversial hypothesis in metabotropic receptors other than olfactory receptors. In the present work, based in part on published experiments from our laboratory using planarians as an experimental organism, I will present a rationale and possible experimental approach for extending this idea to ligand‐gated ion channels. (shrink)

I present here a personal perspective on more than three decades of research into the structural biology of the insulin–receptor interaction. The solution of the three‐dimensional structure of insulin in 1969 provided a detailed understanding of the insulin surfaces involved in self‐assembly. In subsequent years, hundreds of insulin analogues were prepared by insulin chemists and molecular biologists, with the goal of relating the structure to the biological function of the molecule. The design of methods for direct receptor‐binding studies in (...) the 1970s, and the cloning of the receptor in the mid 1980s, provided the required tools for detailed structure–function studies. In the absence of a full three‐dimensional structure of the insulin–receptor complex, I attempt to assemble the existing pieces of the puzzle generated by our and other laboratories, in order to generate a plausible mechanistic model of the insulin–receptor interaction that explains its kinetics and negative cooperativity. BioEssays 26:1351–1362, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

SUR2, similar to SUR1, is a regulatory subunit of the ATP‐sensitive potassium channel (KATP), which plays a key role in numerous important physiological processes and is implicated in various diseases. Recent structural studies have revealed that, like SUR1, SUR2 can undergo ligand‐dependent dynamic conformational changes, transitioning between an inhibitory inward‐facing conformation and an activating occluded conformation. In addition, SUR2 possesses a unique inhibitory Regulatory helix (R helix) that is absent in SUR1. The binding of the activating Mg‐ADP to NBD2 (...) of SUR2 competes with the inhibitory Mg‐ATP, thereby promoting the release of the R helix and initiating the activation process. Moreover, the signal generated by Mg‐ADP binding to NBD2 might be directly transmitted to the TMD of SUR2, prior to NBD dimerization. Furthermore, the C‐terminal 42 residues (C42) of SUR2 might allosterically regulate the kinetics of Mg‐nucleotide binding on NBD2. These distinctive properties render SUR2 intricate sensors for intracellular Mg‐nucleotides. (shrink)

Small gaseous molecules play important roles in biological signaling in both animal and plant physiology. The hydrocarbon gas ethylene has long been known to regulate diverse aspects of plant growth and development, including fruit ripening, leaf senescence and flower abscission. Recent progress has been made toward identifying components involved in ethylene signal transduction in the plant Arabidopsis thaliana. Ethylene is perceived by five receptors that have similarity to two‐component signaling proteins. The hydrophobic amino‐terminus of the receptors binds ethylene, and mutations (...) in this domain both prevent ethylene binding and confer ethylene insensitivity to the plant; the carboxyl‐terminal portion of the receptors has similarity to bacterial his tidine protein kinases. Genetic data suggest a model in which ethylene binding inhibits receptor signaling, yet precisely how these receptors function is unclear. Two of the receptors have been found to associate with a negative regulator of ethylene responses called CTR1, which appears to be a mitogen‐activated protein kinase (MAPK) kinase kinase. BioEssays 23:619–627, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

As targeted proteins that move within the cell, the steroid receptors have become very useful probes for understanding the linked phenomena of protein folding and transport. From the study of steroid receptor‐associated proteins it has become clear over the past two years that these receptors are bound to a multiprotein complex containing at least two heat shock proteins, hsp90 and hsp56. Attachment of receptors to this complex in a cell‐free system appears to require the protein unfolding/folding activity of a third (...) heat shock protein, hsp70. Like the oncogenic tyrosine kinase pp60src, steroid receptors bind to this complex of chaperone proteins at the time of their translation. Binding of the receptor to the hsp90 component of the system occurs through the hormone binding domain and is under strict hormonal control. The hormone binding domain of the receptor acts as a transferable regulatory unit that confers both tight hormonal control and hsp90 binding onto chimaeric proteins. The model of folding and transport being developed for steroid receptors leads to some general suggestions regarding the folding and transport of targeted proteins in the cell. (shrink)

A new high‐resolution structure of a pain‐sensing ion channel, TRPA1, provides a molecular scaffold to understand channel function. Unexpected structural features include a TRP‐domain helix similar to TRPV1, a novel ligand‐binding site, and an unusual C‐terminal coiled coil stabilized by inositol hexakisphosphate (IP6). TRP‐domain helices, which structurally act as a nexus for communication between the channel gates and its other domains, may thus be a feature conserved across the entire TRP family and, possibly, other allosterically‐gated channels. Similarly, the TRPA1 (...) antagonist‐binding site could also represent a druggable location in other ion channels. Combined with known TRPA1 functional properties, the structural role for IP6 leads us to propose that polyphosphate unbinding could act as a molecular kill switch for TRPA1 inactivation. Finally, although packing of the TRPA1 membrane‐proximal region hints at a mechanism for electrophile sensing, the details of how TRPA1 responds to noxious reactive electrophiles and temperature await future studies.Also watch the Video Abstract. (shrink)

The recognition of extracellular molecules by cell surface receptors is the principal mechanism used by cells to sense their environment. Consequently, signals transduced as a result of these interactions make a major contribution to the regulation of cellular phenotype. Historically, particular emphasis has been placed on elucidating the intracellular consequences of growth factor and cytokine binding to cells. In addition to these interactions, however, cells are usually in intimate contact with a further source of complex structural and functional information, (...) namely immobilised extracellular matrix and/or cell surface adhesion proteins. A key question in recent years has been whether cells use the myriad of adhesion protein‐receptor interactions purely for structural and migratory function, or whether these interactions also make a more varied contribution to cell phenotype. Here we review dynamic aspects of the function of one major class of adhesion receptor, the integrins. In particular, we focus on the evidence for shape changes in integrin molecules, the mechanisms responsible for regulating ligand binding, and the signals transduced following integrin occupancy. (shrink)

Androgens (testosterone), acting via the androgen receptor (AR) a nuclear transcription factor, regulate male sexual development and body composition. In addition, AR expression plays an important role in the proliferation of human prostate cancer and confers a better prognosis in breast cancer. AR mRNA stability is central to the regulation of AR expression in prostate and breast cancer cells, and recent studies have demonstrated binding by members of the ELAV/Hu and poly(C) RNA‐binding protein families to a highly conserved (...) UC‐rich element in the 3′‐untranslated region of AR mRNA, with functional impact on AR protein expression. Remarkably, a CAG trinucleotide repeat in exon 1 of the AR, the length of which has been linked to prostate cancer survival, is also a target for multiple RNA‐binding proteins from a variety of human and murine tissues. In this review, we will detail the current knowledge of the mechanisms involved in regulating AR mRNA stability, the nature, potential role and structural biology of several novel AR mRNA–protein interactions, and the implications for novel therapeutics in human prostate cancer. BioEssays 26:672–682, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Current models of insulin binding to the insulin receptor (IR) propose (i) that there are two binding sites on the surface of insulin which engage with two binding sites on the receptor and (ii) that ligand binding involves structural changes in both the ligand and the receptor. Many of the features of insulin binding to its receptor, namely B‐chain helix interactions with the leucine‐rich repeat domain and A‐chain residue interactions with peptide loops from another part (...) of the receptor, are also seen in models of relaxin and insulin‐like peptide 3 binding to their receptors. We show that these principles can likely be extended to the group of mimetic peptides described by Schäffer and coworkers, which are reported to have no sequence identity with insulin. This review summarizes our current understanding of ligand‐induced activation of the IR and highlights the key issues that remain to be addressed. (shrink)

Here we review concepts related to an ensemble description of G-protein-coupled receptors. The ensemble is characterized by both inactive and active states, whose equilibrium populations and exchange rates depend sensitively on ligand, environment, and allosteric factors. This review focuses on the adenosine A2 receptor, a prototypical class A GPCR. 19F Nuclear Magnetic Resonance studies show that apo A2AR is characterized by a broad ensemble of conformers, spanning inactive to active states, and resembling states defined earlier for rhodopsin. In keeping with (...) ideas associated with a conformational selection mechanism, addition of agonist serves to allosterically restrict the overall degrees of freedom at the G protein binding interface and bias both states and functional dynamics to facilitate G protein binding and subsequent activation. While the ligand does not necessarily “induce” activation, it does bias sampling of states, increase the cooperativity of the activation process and thus, the lifetimes of functional activation intermediates, while restricting conformational dynamics to that needed for activation. GPCRs represent a ubiquitous class of transmembrane receptors, responsible for cell signaling and cell homeostasis. Their activation gives rise to conformational changes that allow the receptor to engage downstream partners. Activation can be thought of in terms of a free energy landscape associated with distinct conformers, responsible for the process. Here, the action of ligands is seen to alter this landscape by enabling transitions between key intermediates. (shrink)

The glucocorticoid receptor belongs to an important class of transcription factors that alter the expression of target genes in response to a specific hormone signal. The glucocorticoid receptor can function at least at three levels: (1) recruitment of the general transcription machinery; (2) modulation of transcription factor action, independent of DNA binding, through direct protein‐protein interactions; and (3) modulation of chromatin structure to allow the assembly of other gene regulatory proteins and/or the general transcription machinery on the DNA. This (...) review will focus on the multifaceted nature of protein‐protein interactions involving the glucocorticoid receptor and basal transcription factors, coactivators and other transcription factors, occurring at these different levels of regulation. (shrink)

Recent years have witnessed tremendous growth in the epidermal growth factor (EGF) family of peptide growth factors and the ErbB family of tyrosine kinases, the receptors for these factors. Accompanying this growth has been an increased appreciation for the roles these molecules play in tumorigenesis and in regulating cell proliferation and differentiation during development. Consequently, a significant question has been how diverse biological responses are specified by these hormones and receptors. Here we discuss several characteristics of hormone-receptor interactions and receptor (...) coupling that contribute to specificity: 1) a single EGF family hormone can bind multiple receptors; 2) a single ErbB family receptor can bind multiple hormones; 3) there are three distinct functional groups of EGF family hormones; 4) EGF family hormones can activate receptors in trans, and this heterodimerization diversifies biological responses; 5) ErbB3 requires a receptor partner for signaling; and 6) ErbB family receptors differentially couple to signaling pathways and biological responses. BioEssays 20:41–48, 1998. © 1998 John Wiley & Sons, Inc. (shrink)

The preceding five years have brought remarkable advances in our understanding of the primary structure of drug receptors. The roles of certain amino acid residues in binding drugs and effecting receptor function have been proposed. As even more detailed structures become available, the goal of rational design of drug molecules based on predicted fits between the drug and its receptor will be near at hand. Although none of the classical receptors has yet yielded to X‐ray crystallographic analysis, the methods (...) of molecular biology facilitate the production of the large amounts of these rare proteins necessary for crystallization. Receptor proteins share one fundamental characteristic with allosterically regulated enzymes. Both have the structural flexibility that allows information to be transmitted to distant parts of the molecule. We will discuss recent observations about receptor structure and the dynamic nature of drug receptors, and pose questions about the significance of receptor dynamics for drug design. (shrink)

Signaling by the Epidermal Growth Factor Receptor (EGFR) and related ErbB family receptor tyrosine kinases can be deregulated in human malignancies as the result of mutations in the genes that encode these receptors. The recent identification of EGFR mutations that correlate with sensitivity and resistance to EGFR tyrosine kinase inhibitors in lung and colon tumors has renewed interest in such activating mutations. Here we review current models for ligand stimulation of receptor dimerization and for activation of receptor signaling by receptor (...) dimerization. In the context of these models, we discuss ErbB receptor mutations that affect ligand binding and those that cause constitutive receptor phosphorylation and signaling as a result of constitutive receptor dimerization. We discuss mutations in the cytoplasmic regions that affect enzymatic activity, substrate specificity and coupling to effectors and downstream signaling pathways. Finally, we discuss how emergent mechanisms of ErbB receptor mutational activation could impact the search for clinically relevant ErbB receptor mutations. BioEssays 29:558–565, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Interleukin‐15 (IL‐15) is a pleiotropic cytokine of the 4 α‐helix bundle family, which binds to a receptor complex that displays common elements with the IL‐2 receptor and a unique high‐affinity α chain. This review focuses on juxtacrine and reverse signaling levels in the IL‐15/IL‐15R system. Specifically, we discuss how agonistic stimulation of membrane‐bound IL‐15 induces phosphorylation of members of the MAP kinase family and of focal adhesion kinase (FAK), thereby upregulating processes including cytokine secretion, cell adhesion and migration. In addition, (...) we explore IL‐15 trans‐presentation and intracellular signaling, and define promising molecular targets for future pharmacological intervention in infectious diseases and immunological disorders. These frontiers in IL‐15/IL‐15Rα research serve as highly instructive examples for key concepts, unsolved problems and therapeutic opportunities in juxtacrine and reverse signaling in general. BioEssays 28: 362–377, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Wnt proteins form a family of secreted signaling proteins that play a key role in various developmental events such as cell differentiation, cell migration, cell polarity and cell proliferation. It is currently thought that Wnt proteins activate at least three different signaling pathways by binding to seven transmembrane receptors of the Frizzled family and the co-receptor LRP6. Despite our growing knowledge of intracellular components that mediate a Wnt signal, the molecular events at the membrane have remained rather unclear. Now (...) several publications1-4 indicate that Frizzled receptors are G-protein coupled and kinases were identified that phosphorylate the co-receptor LRP6. These data deepen our understanding of Wnt-mediated signal transduction and provide more insight into how specificity may be achieved. BioEssays 28: 339–343, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

An innovative approach to the production of anti‐receptor antibodies is now being fully exploited for a number of different cell receptors. This approach employs the concept that antibodies directed against pharmacologically active ligands have a three‐dimensional binding site which is somewhat analogous to the natural receptor. Consequently, when anti‐idiotype antibodies are produced against these anti‐ligand antibodies, some of the anti‐idiotypes will comprise a positive three‐dimensional shape which mimics the original ligand. The anti‐idiotypic antibodies generated in this fashion are able (...) to bind to cell surface receptors. This approach has now been successfully applied to peptide hormones, small bio‐active peptides, interferon, viral hemagglutinins, and a number of small neurotransmitter ligands. So far, the boundaries for this working ‘molecular engineering’ concept have not been reached. This concept may also shed light on the processes which take place in the generation of anti‐receptor antibodies in several autoimmune diseases. (shrink)

The activation of leukocytes by bacterial cell wall lipopolysaccharide (LPS) contributes to the pathogenesis of septic shock. It is well established that, in the presence of plasma LPS‐binding protein (LBP), LPS binds with high affinity to CD14. The binding of LPS to CD14 has been associated with the activation of cells, although available evidence indicates that CD14 itself does not transduce intracellular signalling. The physiological function of this interaction is to promote host defense mechanisms of cells to combat (...) the infection and clear LPS from the circulation. At higher concentrations of LPS, however, the activation of cells can take place in the absence of LBP and CD14, presumably through a distinct low‐affinity signalling LPS receptor. On the evidence published by us and others, we propose that in neutrophils, and possibly other leukocytes, L‐selectin can act as a low‐affinity LPS receptor. (shrink)

Interleukin 5 (IL‐5) is a kind of peptide hormone released from T lymphocytes of mammals infected with microorganisms or parasites. It is an acidic glycoprotein with a molecular mass of 40 to 50 kDa that consists of a homodimer of polypeptides. It controls hematopoiesis so that it increases natural immunity. In the mouse, IL‐5 acts on committed B cells to induce differentiation into Ig‐producing cells and on common progenitors for CD5+ pre‐B cells and CD5+ macrophages to support their survival. The (...) antibodies secreted by CD5+ B cells seem to be responsible for the primary protection against the infection with microorganisms or parasites. It also supports the growth and/or differentiation of eosinophil precursor and mature eosinophils, which can be effective for the removal of parasites in combination with the antibodies against them. Murine IL‐5 receptor (IL‐5R) consists of two different polypeptide chains; αL chain and β chain. The IL‐5R α chain is 60 kDa protein that binds IL‐5 with low affinity. The IL‐5R β chain is a 130 kDa protein which does not bind IL‐5 by itself but is necessary to form the high affinity IL‐5R. The β chain was identified by using one of the anti‐IL‐5R mAb and anti‐IL‐3R mAb as the IL‐3R homologue. This β chain is also used as the β chain of GM‐CSF receptor. This fact suggests that there is a common signaling mechanism among these cytokines and efficient cooperation among them. At the same time, these findings may explain the overlapping role of these cytokines in the development of granulocytes. (shrink)

The mechanisms by which most receptor protein‐tyrosine kinases (RTKs) transmit signals are now well established. Binding of ligand results in the dimerization of receptor monomers followed by transphosphorylation of tyrosine residues within the cytoplasmic domains of the receptors. This tidy picture has, however, some strange characters lurking around the edges. Cases have now been identified in which RTKs lack kinase activity, but, despite being “dead” appear to have roles in signal transduction. Even stranger are the cases in which genes (...) encoding RTKs produce protein products consisting of only a portion of the kinase domain. At least one such “fractured” RTK appears to be involved in signal transduction. Here we describe how these strange molecules might function and discuss the questions associated with their evolution. BioEssays 23:69–76, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Alpha‐fetoprotein (AFP)AFP, alpha‐fetoprotein; T3R, thyroid hormone (triiodothyronine) receptor; RAR, retionic acid receptor; erbA, putative thyroid hormone receptor proto‐oncogene products; VDR, vitamin D receptor; MR, mineralocorticoid receptor; GR, glucocorticoid receptor; PR, progesterone receptor; AR, androgen receptor; HRE, hormone response element on DNA; RXR, retionic‐X‐receptor; RAP, receptor auxiliary (accessory) proteins; E, estrogen. is a tumor‐associated fetal marker, associated both with tumor growth and with birth defects. AFP, whose precise function is unknown, has been classified as belonging to a protein superfamily together with (...) albumin and vitamin D‐binding (Gc) protein. AFP has been shown to bind various ligands in vitro including fatty acids, estrogens, thyroid hormones and retinoic acids. The steroid/thyroid nuclear receptor superfamily of proteins has recently become a major focus of biomedical investigation regarding regulation of gene expression. These receptors are thought to bind to DNA‐hormone response elements (HRE) that affect growth, development, differentiation, reproduction and homeostasis. The HREs are known to share DNA sequences with the various members of the nuclear receptor superfamily. In the present report, the possibility of a leucine‐zipper dimerization (heptad) motif in the carboxy‐terminal third domain of both rodent and human AFP is postulated. The presence of nine such hydrophobic repeats in the third domain of the AFP molecule mimics the heptad dimerization repeats found in the retinoic acid, thyroid, e‐erbA and other members of the nuclear receptor superfamily. Computer analysis revealed that the most conservative matching occurred between AFP and the retinoic acid class of receptors. However, other superfamily members displayed 40–60% homology with 5 of 9 AFP heptads. These findings could provide a possible mechanism for explaining the growth‐regulatory properties (both inhibition and enhancement) that have been ascribed to AFP in the last decade. (shrink)

Cell proliferation in response to growth factors is mediated by specific high affinity receptors. Ligand‐binding by receptors of the protein tyrosine kinase family results in the stimulation of several intracellular signal transduction pathways. Key signalling enzymes are recruited to the plasma membrane through the formation of stable complexes with activated receptors. These interactions are mediated by the conserved, non‐catalytic SH2 domains present in the signalling molecules, which bind with high affinity and specificity to tyrosine‐phosphorylated sequences on the receptors. The (...) assembly of enzyme complexes is emerging as a major mechanism of signal transduction and may regulate the pleiotropic effects of growth factors. (shrink)

Nicotinic acetylcholine receptors (nAChRs) are ligand‐gated ion channels that bring about a diversity of fast synaptic actions. Analysis of the Caenorhabditis elegans genome has revealed one of the most‐extensive and diverse nAChR gene families known, consisting of at least 27 subunits. Striking variation with possible functional implications has been observed in normally conserved motifs at the acetylcholine‐binding site and in the channel‐lining region. Some nAChR subunits are particular to neurons whilst others are present in both neurons and muscles. The (...) localization of subunits in non‐synaptic regions suggests novel roles for nAChRs. Genetic and heterologous expression studies have identified a subset of nAChR subunits that are important drug targets while the study of mutants has identified genes functionally‐linked to nAChRs. Future studies using C. elegans offer the prospect of increasing our understanding of the functional diversity of a complex nAChR gene family as well as addressing the role of nAChRs and associated proteins in human disorders. BioEssays 26:39–49, 2004.© 2003 Wiley Periodicals, Inc. (shrink)

The gelsolin gene family encodes a number of higher eukaryotic actin-binding proteins that are thought to function in the cytoplasm by severing, capping, nucleating or bundling actin filaments. Recent evidence, however, suggests that several members of the gelsolin family may have adopted unexpected nuclear functions including a role in regulating transcription. In particular, flightless I, supervillin and gelsolin itself have roles as coactivators for nuclear receptors, despite the fact that their divergence appears to predate the evolutionary appearance of nuclear (...) receptors. Flightless I has been shown to bind both actin and the actin-related BAF53a protein, which are subunits of SWI/SNF-like chromatin remodelling complexes. The primary sequences of some actin-related proteins such as BAF53a exhibit conservation of residues that, in actin itself, are known to interact with gelsolin-related proteins. In summary, there is a growing body of evidence supporting a biological role in the nucleus for actin, Arps and actin-binding proteins and, in particular, the gelsolin family of actin-binding proteins. (c) 2005 Wiley Periodicals, Inc. (shrink)

This volume brings together about 50 scientists and researchers from the four corners of the world to redefine and anticipate tomorrow's values, and reflect on ...

In his preface to Human, Too Human Nietzsche wrote: ‘My books have been labelled the school of suspicion … ‘ Predicted and desired by Nietzsche, the age of suspicion does seem to be one of the labels that best characterize the century that has just closed. And symptomatically it was used a few decades later in France to describe writers’ interrogations about the novel as a literary genre, its facilities and conventions, its easy determinisms, as well as the exorbitant power (...) of the novelist-demiurge. Is it necessary to recall that the forerunner to the nouveau roman, written by Nathalie Sarraute in the 1930s, was in fact entitled L’Ère du soupçon? It is impossible to emphasize enough this close concordance between philosophical questioning and aesthetic interrogations, particularly in the notion of avant-garde, which is indispensable for thinking about intellectual and political renewal. It is true that the 20th century was the century of the universal declaration of human rights, but also the century of rejection of norms inherited from philosophical, literary, cultural, religious or scientific traditions, which came to be suspected of providing only off-the-peg elements for thought and action at a time when the world was changing and required new forms of thinking. (shrink)

Résumé Le cheminement de la pensée occidentale, depuis plus d’un siècle, a vu : la mort de Dieu, la chute des idéologies politiques qui semblaient avoir pris le relais des valeurs « divines », la solitude de l’individu désorienté. Le malaise de l’individu serait le symptôme d’une remise en question de la notion même d’être humain. En reprenant la critiques de l’humanisme introduite par Nietzsche, Sloterdijk fait ressortir que l’homme aurait échappé à la bestialité par les moyens mêmes qu’il emploie (...) pour apprivoiser les animaux et les mettre à son service. Que dire de ce que la recherche permet actuellement de faire sur l’être humain? La manipulation du vivant a fait émerger la possibilité d’une fabrique de l’être humain. Les choix que nous avons à faire quant au devenir de l’humain restent éminemment politiques. Le terme d’humanisme est complexe : il est deux types d’humanisme. Celui qui conçoit l’humain comme une essence. La seconde forme considère qu’il n’y a pas de nature humaine, que l’on devient humain. Le monde humain est ouvert à la création, mais fragilisé parce que placé sous notre responsabilité. (shrink)

In his preface to Human, Too Human Nietzsche wrote: ‘My books have been labelled the school of suspicion … ‘ Predicted and desired by Nietzsche, the age of suspicion does seem to be one of the labels that best characterize the century that has just closed. And symptomatically it was used a few decades later in France to describe writers’ interrogations about the novel as a literary genre, its facilities and conventions, its easy determinisms, as well as the exorbitant power (...) of the novelist-demiurge. Is it necessary to recall that the forerunner to the nouveau roman, written by Nathalie Sarraute in the 1930s, was in fact entitled L’Ère du soupçon? It is impossible to emphasize enough this close concordance between philosophical questioning and aesthetic interrogations, particularly in the notion of avant-garde, which is indispensable for thinking about intellectual and political renewal. It is true that the 20th century was the century of the universal declaration of human rights, but also the century of rejection of norms inherited from philosophical, literary, cultural, religious or scientific traditions, which came to be suspected of providing only off-the-peg elements for thought and action at a time when the world was changing and required new forms of thinking. (shrink)

Severe acute respiratory syndrome‐coronavirus (SARS‐CoV)‐2′s origin is still controversial. Genomic analyses show SARS‐CoV‐2 likely to be chimeric, most of its sequence closest to bat CoV RaTG13, whereas its receptor binding domain (RBD) is almost identical to that of a pangolin CoV. Chimeric viruses can arise via natural recombination or human intervention. The furin cleavage site in the spike protein of SARS‐CoV‐2 confers to the virus the ability to cross species and tissue barriers, but was previously unseen in other SARS‐like (...) CoVs. Might genetic manipulations have been performed in order to evaluate pangolins as possible intermediate hosts for bat‐derived CoVs that were originally unable to bind to human receptors? Both cleavage site and specific RBD could result from site‐directed mutagenesis, a procedure that does not leave a trace. Considering the devastating impact of SARS‐CoV‐2 and importance of preventing future pandemics, researchers have a responsibility to carry out a thorough analysis of all possible SARS‐CoV‐2 origins. (shrink)

The basic elements of faceted thesauri are described, together with a review of their origins and some prominent examples. Their use in browsing and searching applications is discussed. Faceted thesauri are distinguished from faceted classification schemes, while acknowledging the close similarities. The paper concludes by comparing faceted thesauri and related knowledge organization systems to ontologies and discussing appropriate areas of use.

Neurobiology studies mechanisms of cell signalling. A key question is how cells recognise specific signals. In this context, olfaction has become an important experimental system over the past 25 years. The olfactory system responds to an array of structurally diverse stimuli. The discovery of the olfactory receptors (ORs), recognising these stimuli, established the olfactory pathway as part of a greater group of signalling mechanisms mediated by G-protein-coupled receptors (GPCRs). GPCRs are the largest protein family in the mammalian genome and involved (...) in numerous fundamental physiological processes. The OR family exhibits two characteristics that make them an excellent model system to understand GPCRs: its size and the structural diversity of its members. Research on the OR binding site investigates what amino acid sequences determine the receptor-binding capacity. This promises a better understanding of how the basic genetic makeup of GPCRs relates to their diversification in ligand-binding capacities. (shrink)

The origin of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is the subject of many hypotheses. One of them, proposed by Segreto and Deigin, assumes artificial chimeric construction of SARS‐CoV‐2 from a backbone of RaTG13‐like CoV and receptor binding domain (RBD) of a pangolin MP789‐like CoV, followed by serial cell or animal passage. Here we show that this hypothesis relies on incorrect or weak assumptions, and does not agree with the results of comparative genomics analysis. The genetic divergence between (...) SARS‐CoV‐2 and both its proposed ancestors is too high to have accumulated in a lab, given the timeframe of several years. Furthermore, comparative analysis of S‐protein gene sequences suggests that the RBD of SARS‐CoV‐2 probably represents an ancestral non‐recombinant variant. These and other arguments significantly weaken the hypothesis of a laboratory origin for SARS‐CoV‐2, while the hypothesis of a natural origin is consistent with all available genetic and experimental data. (shrink)

Resistance to inhibitors of cholinesterase 8A (Ric‐8A) is a prominent non‐receptor GEF and a chaperone of G protein α‐subunits (Gα). Recent studies shed light on the structure of Ric‐8A, providing insights into the mechanisms underlying its interaction with Gα. Ric‐8A is composed of a core armadillo‐like domain and a flexible C‐terminal tail. Interaction of a conserved concave surface of its core domain with the Gα C‐terminus appears to mediate formation of the initial Ric‐8A/GαGDP intermediate, followed by the formation of a (...) stable nucleotide‐free complex. The latter event involves a large‐scale dislocation of the Gα α5‐helix that produces an extensive primary interface and disrupts the nucleotide‐binding site of Gα. The distal portion of the C‐terminal tail of Ric‐8A forms a smaller secondary interface, which ostensibly binds the switch II region of Gα, facilitating binding of GTP. The two‐site Gα interface of Ric‐8A is distinct from that of GPCRs, and might have evolved to support the chaperone function of Ric‐8A. (shrink)

Disabled‐2 (Dab2) is a multimodular scaffold protein with signaling roles in the domains of cell growth, trafficking, differentiation, and homeostasis. Emerging evidences place Dab2 as a novel modulator of cell–cell interaction; however, its mode of action has remained largely elusive. In this review, we highlight the relevance of Dab2 function in cell signaling and development and provide the most recent and comprehensive analysis of Dab2's action as a mediator of homotypical and heterotypical interactions. Accordingly, Dab‐2 controls the extent of platelet (...) aggregation through various motifs within its N‐terminus. Dab2 interacts with the cytosolic tail of the integrin receptor blocking inside‐out signaling, whereas extracellular Dab2 competes with fibrinogen for integrin αIIbβ3 receptor binding and, thus, modulates outside‐in signaling. An additional level of regulation results from Dab2's association with cell surface lipids, an event that defines the extent of cell–cell interactions. As a multifaceted regulator, Dab2 acts as a mediator of endocytosis through its association with the [FY]xNPx[YF] motifs of internalized cell surface receptors, phosphoinositides, and clathrin. Other emerging roles of Dab2 include its participation in developmental mechanisms required for tissue formation and in modulation of immune responses. This review highlights the various novel mechanisms by which Dab2 mediates an array of signaling events with vast physiological consequences. (shrink)