共查询到20条相似文献,搜索用时 31 毫秒
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An enigmatic yet fundamental principle of signal transduction is that parallel signaling pathways assembled from a common repertoire of enzymes are able to propagate diverse physiological responses. A key feature of such a mechanism is that separate signaling pathways are organized into localized transduction units, each tailored to respond optimally to a particular signal. Protein-protein interactions maintained by anchoring, adapter and scaffolding proteins provide the molecular glue that holds these signal transduction units together. A major objective of the signaling community is to ascertain how signals flow through compartmentalized transduction units that contain transmembrane receptors, protein kinases, phosphatases and their substrates. 相似文献
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A fundamental issue in cell biology is how signals are transmitted across membranes. A variety of transmembrane receptors, including multichain immune recognition receptors, lack catalytic activity and require Src family kinases (SFKs) for signal transduction. However, many receptors only bind and activate SFKs after ligand-induced receptor dimerization. This presents a conundrum: How do SFKs sense the dimerization of receptors to which they are not already bound? Most proposals for resolving this enigma invoke additional players, such as lipid rafts or receptor conformational changes. Here we used simple thermodynamics to show that SFK activation is a natural outcome of clustering of receptors with SFK phosphorylation sites, provided that there is phosphorylation-dependent receptor-SFK association and an SFK bound to one receptor can phosphorylate the second receptor or its associated SFK in a dimer. A simple system of receptor, SFK, and an unregulated protein tyrosine phosphatase (PTP) can account for ligand-induced changes in phosphorylation observed in cells. We suggest that a core signaling system comprising a receptor with SFK phosphorylation sites, an SFK, and an unregulated PTP provides a robust mechanism for transmembrane signal transduction. Other events that regulate signaling in specific cases may have evolved for fine-tuning of this basic mechanism. 相似文献
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Bouvier M 《Nature reviews. Neuroscience》2001,2(4):274-286
Examples of G-protein-coupled receptors that can be biochemically detected in homo- or heteromeric complexes are emerging at an accelerated rate. Biophysical approaches have confirmed the existence of several such complexes in living cells and there is strong evidence to support the idea that dimerization is important in different aspects of receptor biogenesis and function. While the existence of G-protein-coupled-receptor homodimers raises fundamental questions about the molecular mechanisms involved in transmitter recognition and signal transduction, the formation of heterodimers raises fascinating combinatorial possibilities that could underlie an unexpected level of pharmacological diversity, and contribute to cross-talk regulation between transmission systems. Because G-protein-coupled receptors are major pharmacological targets, the existence of dimers could have important implications for the development and screening of new drugs. Here, we review the evidence supporting the existence of G-protein-coupled-receptor dimerization and discuss its functional importance. 相似文献
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Signal transduction systems based on tyrosine phosphorylation are central to cell–cell communication in multicellular organisms. Typically, in such a system, the signal is initiated by activating tyrosine kinases associated with transmembrane receptors, which induces tyrosine phosphorylation of the receptor and/or associated proteins. The phosphorylated tyrosines then serve as docking sites for the binding of various downstream effector proteins. It has long been observed that the cooperative association of the receptors and effectors produces higher-order protein assemblies (clusters) following signal activation in virtually all phosphotyrosine signal transduction systems. However, mechanistic studies on how such clustering processes affect signal transduction outcomes have only emerged recently. Here we review current progress in decoding the biophysical consequences of clustering on the behavior of the system, and how clustering affects how these receptors process information. 相似文献
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Kathleen Postle 《Journal of bioenergetics and biomembranes》1993,25(6):591-601
TonB protein couples cytoplasmic membrane electrochemical potential to active transport of iron-siderophore complexes and vitamin B12 through high-affinity outer membrane receptors of Gram-negative bacteria. The mechanism of energy transduction remains to be determined, but important concepts have already begun to emerge. Consistent with its function, TonB is anchored in the cytoplasmic membrane by its uncleaved amino terminus while largely occupying the periplasm. Both the connection to the cytoplasmic membrane and the amino acid sequences of the anchor are essential for activity. TonB directly associates with a number of envelope proteins, among them the outer membrane receptors and cytoplasmic membrane protein ExbB. ExbB and TonB interact through their respective transmembrane domains. ExbB is proposed to recycle TonB to an active conformation following energy transduction to the outer membrane. TonB most likely associates with the outer membrane receptors through its carboxy terminus, which is required for function. In contrast, the novel prolinerich region of TonB can be deleted without affecting function. A model that incorporates this information, as well as tempered speculation, is presented. 相似文献
7.
《朊病毒》2013,7(3):184-189
A variety of signaling pathways, in particular with roles in cell fate and host defense, operate by a prion-like mechanism consisting in the formation of open-ended oligomeric signaling complexes termed signalosomes. This mechanism emerges as a novel paradigm in signal transduction. Among the proteins forming such signaling complexes are the Nod-like receptors (NLR), involved in innate immunity. It now appears that the [Het-s] fungal prion derives from such a cell-fate defining signaling system controlled by a fungal NLR. What was once considered as an isolated oddity turns out to be related to a conserved and widespread signaling mechanism. Herein, we recall the relation of the [Het-s] prion to the signal transduction pathway controlled by the NWD2 Nod-like receptor, leading to activation of the HET-S pore-forming cell death execution protein. We explicit an evolutionary scenario in which formation of the [Het-s] prion is the result of an exaptation process or how a loss-of-function mutation in a pore-forming cell death execution protein (HET-S) has given birth to a functional prion ([Het-s]). 相似文献
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Kralisz U 《Postepy biochemii》2005,51(3):308-317
Adaptor proteins play a pivotal role in the regulation of signal transduction events elicited after the engagement of cell surface receptors. Platelets exhibit a number of integral membrane receptors capable of initiating a cellular response. These include collagen receptors, von Willebrand factor receptors, the fibrinogen receptor, and a number of G-protein coupled receptors, such as those for thrombin and ADP. The primary function of platelet receptors is the translation of externally applied signals into appropriate responses leading to platelet activation being a prerequisite for normal hemostasis. Multitude of signalling pathways described in platelets is based on the interaction of compounds of many different categories, such as transmembrane receptors, protein kinases, protein phoshatases, G-proteins, transmembrane and cytosolic adaptor proteins, phosphoinositides, cyclic AMP or GMP. Adaptor proteins lack intrinsic effector function, but contain distinct molecular domains, which mediate protein-protein and protein-lipid interactions. These molecules thus serve as a scaffolding, around which effectors and their substrates are assembled into three-dimensional signaling complexes. Adaptor proteins integrate receptor-mediated signals at intracellular levels and couple signaling receptors to cytosolic signaling pathways. While the function of adaptor proteins is well established in immune cells, the knowledge about their role in platelet activation is still at the onset Over the last decade numerous adaptor proteins have been identified in platelets and shown to be involved in accurate assembly of intracellular signaling complexes. Collagen-induced platelet intracellular signaling through GPVI resembles the functional response of B- and T-cell antigen receptors and is the best described in the literature. This review focuses on the structure and functional role of the most extensively studied adaptor proteins during platelet activation induced by physiological agonists. 相似文献
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A variety of signaling pathways, in particular with roles in cell fate and host defense, operate by a prion-like mechanism consisting in the formation of open-ended oligomeric signaling complexes termed signalosomes. This mechanism emerges as a novel paradigm in signal transduction. Among the proteins forming such signaling complexes are the Nod-like receptors (NLR), involved in innate immunity. It now appears that the [Het-s] fungal prion derives from such a cell-fate defining signaling system controlled by a fungal NLR. What was once considered as an isolated oddity turns out to be related to a conserved and widespread signaling mechanism. Herein, we recall the relation of the [Het-s] prion to the signal transduction pathway controlled by the NWD2 Nod-like receptor, leading to activation of the HET-S pore-forming cell death execution protein. We explicit an evolutionary scenario in which formation of the [Het-s] prion is the result of an exaptation process or how a loss-of-function mutation in a pore-forming cell death execution protein (HET-S) has given birth to a functional prion ([Het-s]). 相似文献
10.
Pucadyil TJ Kalipatnapu S Harikumar KG Rangaraj N Karnik SS Chattopadhyay A 《Biochemistry》2004,43(50):15852-15862
Serotonergic signaling appears to play a key role in the generation and modulation of various cognitive, behavioral, and developmental processes. The serotonin(1A) receptor is an important member of the superfamily of seven transmembrane domain G-protein-coupled receptors and is the most extensively studied among the serotonin receptors. Several aspects of serotonin(1A) receptor biology such as cellular distribution and signal transduction characteristics are technically difficult to address in living cells on account of the inability to optically track these receptors with fluorescence-based techniques. We describe here the characterization of the serotonin(1A) receptor tagged to the enhanced yellow fluorescent protein (EYFP) stably expressed in Chinese hamster ovary (CHO) cells. These receptors were found to be essentially similar to the native receptor in pharmacological assays and can therefore be used to reliably explore aspects of receptor biology such as cellular distribution and dynamics on account of their intrinsic fluorescent properties. Analysis of the cell surface dynamics of these receptors by fluorescence recovery after photobleaching (FRAP) experiments has provided novel insight into the molecular mechanism of signal transduction of serotonin(1A) receptors in living cells. Interestingly, addition of pharmacologically well-characterized ligands or activators of G-proteins altered the diffusion characteristics of the receptor in a manner consistent with the G-protein activation model. These results demonstrate, for the first time, that membrane dynamics of this receptor is modulated in a G-protein-dependent manner. 相似文献
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Lutz Birnbaumer 《生物化学与生物物理学报:生物膜》2007,1768(4):772-793
The first 15 years, or so, brought the realization that there existed a G protein coupled signal transduction mechanism by which hormone receptors regulate adenylyl cyclases and the light receptor rhodopsin activates visual phosphodiesterase. Three G proteins, Gs, Gi and transducin (T) had been characterized as αβγ heterotrimers, and Gsα-GTP and Tα-GTP had been identified as the sigaling arms of Gs and T. These discoveries were made using classical biochemical approaches, and culminated in the purification of these G proteins. The second 15 years, or so, are the subject of the present review. This time coincided with the advent of powerful recombinant DNA techniques. Combined with the classical approaches, the field expanded the repertoire of G proteins from 3 to 16, discovered the superfamily of seven transmembrane G protein coupled receptors (GPCRs) - which is not addressed in this article - and uncovered an amazing repertoire of effector functions regulated not only by αGTP complexes but also by βγ dimers. Emphasis is placed in presenting how the field developed with the hope of conveying why many of the new findings were made. 相似文献
12.
Kabbani N 《Proteomics》2008,8(19):4146-4155
Receptors represent an abundant class of integral membrane proteins that transmit information on various types of signals within the cell. Assemblages of receptors and their interacting proteins (receptor complexes) have emerged as important units of signal transduction for various types of receptors including G protein coupled, ligand-gated ion channel, and receptor tyrosine kinase. This review aims to summarize the major approaches and findings of receptor proteomics. Isolation and characterization of receptor complexes from cells has become common using the methods of immunoaffinity-, ligand-, and tag-based chromatography followed by MS for the analysis of enriched receptor preparations. In addition, tools such as stable isotope labeling have contributed to understanding quantitative properties and PTMs to receptors and their interacting proteins. As data from studies on receptor-protein interactions considerably expands, complementary approaches such as bioinformatics and computational biology will undoubtedly play a significant role in defining cellular and network functions for various types of receptor complexes. Findings from receptor proteomics may also shed light on the mechanism of action for pharmacological drugs and can be of value in understanding molecular pathologies of disease states. 相似文献
13.
Protein 4.1 (also called band 4.1 or simply 4.1) was originally identified as an abundant protein of the human erythrocyte, in which it stabilizes the spectrin/actin cytoskeleton. The protein and its relatives have since been found in many cell types of metazoan organisms and they are often concentrated in the nucleus, as well as in cell-cell junctions. They form multimolecular complexes with transmembrane and membrane-associated proteins, and these complexes may be important for both structural stability and signal transduction at sites of cell contact. 相似文献
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Reis RI Santos EL Pesquero JB Oliveira L Schanstra JP Bascands JL Pecher C Paiva AC Costa-Neto CM 《Regulatory peptides》2007,140(1-2):32-36
Most of the classical physiological effects of the octapeptide angiotensin II (AngII) are produced by activating the AT1 receptor which belongs to the G-protein coupled receptor family (GPCR). Peptidic GPCRs may be functionally divided in three regions: (i) extracellular domains involved in ligand binding; (ii) intracellular domains implicated in agonist-induced coupling to G protein and (iii) seven transmembrane domains (TM) involved in signal transduction. The TM regions of such receptors have peculiar characteristics such as the presence of proline residues. In this project we aimed to investigate the participation of two highly conserved proline residues (Pro82 and Pro162), located in TM II and TM IV, respectively, in AT1 receptor signal transduction. Both mutations did not cause major alterations in AngII affinity. Functional assays indicated that the P162A mutant did not influence the signal transduction. On the other hand, a potent deleterious effect of P82A mutation on signal transduction was observed. We believe that the Pro82 residue is crucial to signal transduction, although it is not possible to say yet if this is due to a direct participation or if due to a structural rearrangement of TM II. In this last hypothesis, the removal of proline residue might be correlated to a removal of a kink, which in turn can be involved in the correct positioning of residues involved in signal transduction. 相似文献
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Ioanna Bethani Sigrid S Skånland Ivan Dikic Amparo Acker‐Palmer 《The EMBO journal》2010,29(16):2677-2688
The spatial organization of transmembrane receptors is a critical step in signal transduction and receptor trafficking in cells. Transmembrane receptors engage in lateral homotypic and heterotypic cis‐interactions as well as intercellular trans‐interactions that result in the formation of signalling foci for the initiation of different signalling networks. Several aspects of ligand‐induced receptor clustering and association with signalling proteins are also influenced by the lipid composition of membranes. Thus, lipid microdomains have a function in tuning the activity of many transmembrane receptors by positively or negatively affecting receptor clustering and signal transduction. We review the current knowledge about the functions of clustering of transmembrane receptors and lipid–protein interactions important for the spatial organization of signalling at the membrane. 相似文献
17.
Seven transmembrane domain G-protein-coupled receptors constitute the largest family of proteins in mammals. Signal transduction
events mediated by such receptors are the primary means by which cells communicate with and respond to their external environment.
The major paradigm in this signal transduction process is that stimulation of the receptor leads to the recruitment and activation
of heterotrimeric GTP-binding proteins. These initial events, which are fundamental to all types of G-protein-coupled receptor
signaling, occur at the plasma membrane via protein–protein interactions. As a result, the dynamics of the activated receptor
on cell surfaces represents an important determinant in its encounter with G-proteins, and has significant impact on the overall
efficiency of the signal transduction process. We have monitored the cell surface dynamics of the serotonin1A receptor, an important member of the G-protein-coupled receptor superfamily, in relation to its interaction with G-proteins.
Fluorescence recovery after photobleaching experiments carried out with the receptor tagged to the enhanced yellow fluorescent
protein indicate that G-protein activation alters the diffusion properties of the receptor in a manner suggesting the activation
process leads to dissociation of G-proteins from the receptor. This result demonstrates that the cell surface dynamics of
the serotonin1A receptor is modulated in a G-protein-dependent manner. Importantly, this result could provide the basis for a sensitive and
powerful approach to assess receptor/G-protein interaction in an intact cellular environment. 相似文献
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George Panayotou Michael D. Waterfield 《BioEssays : news and reviews in molecular, cellular and developmental biology》1993,15(3):171-177
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. 相似文献
19.
Living organisms use complex pathways of signal perception and transduction to respond to stimuli in their environments. In plants, putative signal transduction components have been identified through mutant screens and comparative analysis of genome sequences of model eukaryotes. Several pieces in a large series of puzzles have now been identified and a current challenge is to determine how these pieces interconnect. Functional analysis of the encoded proteins has necessitated a change from genetic to biochemical approaches. In recent years, the application of techniques such as two-hybrid screening and epitope tagging has facilitated the study of protein-protein interactions and has increased our understanding of cellular signalling mechanisms. One focus of present research is the ubiquitin/proteasome-mediated degradation of proteins. Increasing evidence suggests this is a control common to many plant signalling pathways including development and responsiveness to hormones, light and sucrose. A central challenge in the study of plant disease resistance has been to identify protein complexes that contain host defence proteins and pathogenicity factors. In this review we summarize the latest developments in these areas where the existence of protein complexes has been demonstrated to be of fundamental importance in plant signalling. 相似文献
20.
Protein-protein interactions define specificity in signal transduction and these interactions are central to transmembrane signaling by G-protein-coupled receptors (GPCRs). It is not quite clear, however, whether GPCRs and the regulatory trimeric G-proteins behave as freely and independently diffusible molecules in the plasma membrane or whether they form some preassociated complexes. Here we used clear-native polyacrylamide gel electrophoresis (CN-PAGE) to investigate the presumed coupling between thyrotropin-releasing hormone (TRH) receptor and its cognate G(q/11) protein in HEK293 cells expressing high levels of these proteins. Under different solubilization conditions, the TRH receptor (TRH-R) was identified to form a putative pentameric complex composed of TRH-R homodimer and G(q/11) protein. The presumed association of TRH-R with G(q/11)α or Gβ proteins in plasma membranes was verified by RNAi experiments. After 10- or 30-min hormone treatment, TRH-R signaling complexes gradually dissociated with a concomitant release of receptor homodimers. These observations support the model in which GPCRs can be coupled to trimeric G-proteins in preassembled signaling complexes, which might be dynamically regulated upon receptor activation. The precoupling of receptors with their cognate G-proteins can contribute to faster G-protein activation and subsequent signal transfer into the cell interior. 相似文献