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Ciruela F Ferré S Casadó V Cortés A Cunha RA Lluis C Franco R 《Cellular and molecular life sciences : CMLS》2006,63(21):2427-2431
Since 1990 it has been known that dimers are the basic functional form of nearly all G-protein-coupled receptors (GPCRs) and
that homo- and heterodimerization may play a key role in correct receptor maturation and trafficking to the plasma membrane.
Nevertheless, homo- and heterodimerization of GPCR has become a matter of debate especially in the search for the precise
physiological meaning of this phenomenon. This article focuses on how heterodimerization of adenosine A1 and A2A receptors, which are coupled to apparently opposite signalling pathways, allows adenosine to exert a fine-tuning modulation
of striatal glutamatergic neurotransmission, providing a switch mechanism by which low and high concentrations of adenosine
inhibit and stimulate, respectively, glutamate release.
Received 8 May 2006; received after revision 19 June 2006; accepted 17 July 2006 相似文献
3.
Ellis JA 《Cellular and molecular life sciences : CMLS》2006,63(23):2702-2709
Emery-Dreifuss muscular dystrophy (EDMD) is a neuromuscular degenerative condition with an associated dilated cardiomyopathy
and cardiac conduction defect. It can be inherited in either an X-linked or autosomal manner by mutations in the nuclear proteins
emerin and lamin A/C, respectively. Traditionally muscular dystrophies were associated with defects in sarcolemma-associated
proteins and, therefore, a nuclear connection suggested the existence of novel signalling pathways associated with this group
of diseases. Subsequently, other mutations in the lamin A/C gene were attributed to a range of tissue-specific degenerative
conditions, collectively known as the ‘laminopathies’. Therefore, any proposed hypothesis underlying the molecular mechanism
of EDMD needs to include this anomaly. As we celebrate the 10th anniversary of the identification of emerin as a component
of the nuclear envelope, I discuss here the available evidence that currently implicates EDMD as arising from perturbations
in myogenic regulatory pathways, causing temporal delays in both cell cycle progression and muscle regeneration.
Received 25 May 2006; received after revision 22 June 2006; accepted 22 August 2006 相似文献
4.
Nitric oxide plays a crucial role in cardiovascular homeostasis, with important vasodilatory, anti-thrombotic and anti-atherogenic
properties. β-Adrenergic receptors (βARs), present on a wide variety of cardiovascular cells, including vascular endothelial
cells, platelets, cardiac myocytes and leukocytes, have long been established as key players in maintaining cardiovascular
homeostatic control. During the last few years a wealth of evidence has emerged which directly links stimulation of these
cardiovascular βARs to nitric oxide (NO) generation, suggesting a new and important mechanism of adrenergic control of cardiovascular
function. This review explores the cardiovascular cell systems in which this coupling of βARs and NO occurs, the intracellular
signalling and regulatory mechanisms involved and the abnormalities in βAR-NO oxide coupling found in cardiovascular disease
states.
Received 30 September 2005; received after revision 24 November 2005; accepted 24 January 2006 相似文献
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Identification of rate-limiting steps or components of intracellular second messenger systems holds promise to effectively
interfere with these pathways under pathological conditions. The emerging literature on a recently identified family of signalling
regulator proteins, called tribbles gives interesting clues for how these proteins seem to link several ‘independent’ signal
processing systems together. Via their unique way of action, tribbles co-ordinate the activation and suppression of the various
interacting signalling pathways and therefore appear to be key in determining cell fate while responding to environmental
challenges. This review summarises our current understanding of tribbles function and also provides an evolutionary perspective
on the various tribbles genes.
Received 10 January 2006; received after revision 20 March 2006; accepted 5 April 2006 相似文献
6.
Myelin basic protein: a multifunctional protein 总被引:1,自引:1,他引:0
Boggs JM 《Cellular and molecular life sciences : CMLS》2006,63(17):1945-1961
Myelin basic protein (MBP), the second most abundant protein in central nervous system myelin, is responsible for adhesion
of the cytosolic surfaces of multilayered compact myelin. A member of the ‘intrinsically disordered’ or conformationally adaptable
protein family, it also appears to have several other functions. It can interact with a number of polyanionic proteins including
actin, tubulin, Ca2+-calmodulin, and clathrin, and negatively charged lipids, and acquires structure on binding to them. It may act as a membrane
actin-binding protein, which might allow it to participate in transmission of extracellular signals to the cytoskeleton in
oligodendrocytes and tight junctions in myelin. Some size isoforms of MBP are transported into the nucleus and thus they may
also bind polynucleotides. Extracellular signals received by myelin or cultured oligodendrocytes cause changes in phosphorylation
of MBP, suggesting that MBP is also involved in signaling. Further study of this very abundant protein will reveal how it
is utilized by the oligodendrocyte and myelin for different purposes.
Received 2 March 2006; received after revision 12 April 2006; accepted 16 May 2006 相似文献
7.
Sebastian Fiedler Jana Broecker Sandro Keller 《Cellular and molecular life sciences : CMLS》2010,67(11):1779-1798
Separation of cells and organelles by bilayer membranes is a fundamental principle of life. Cellular membranes contain a baffling
variety of proteins, which fulfil vital functions as receptors and signal transducers, channels and transporters, motors and
anchors. The vast majority of membrane-bound proteins contain bundles of α-helical transmembrane domains. Understanding how
these proteins adopt their native, biologically active structures in the complex milieu of a membrane is therefore a major
challenge in today’s life sciences. Here, we review recent progress in the folding, unfolding and refolding of α-helical membrane
proteins and compare the molecular interactions that stabilise proteins in lipid bilayers. We also provide a critical discussion
of a detergent denaturation assay that is increasingly used to determine membrane-protein stability but is not devoid of conceptual
difficulties. 相似文献
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Temussi PA 《Cellular and molecular life sciences : CMLS》2006,63(16):1876-1888
A few proteins, discovered mainly in tropical fruits, have a distinct sweet taste. These proteins have played an important
role towards a molecular understanding of the mechanisms of taste. Owing to the huge difference in size, between most sweeteners
and sweet proteins, it was believed that they must interact with a different receptor from that of small molecular weight
sweeteners. Recent modelling studies have shown that the single sweet taste receptor has multiple active sites and that the
mechanism of interaction of sweet proteins is intrinsically different from that of small sweeteners. Small molecular weight
sweeteners occupy small receptor cavities inside two subdomains of the receptor, whereas sweet proteins can interact with
the sweet receptor according to a mechanism called the ‘wedge model’ in which they bind to a large external cavity. This review
describes these mechanisms and outlines a history of sweet proteins.
Received 11 February 2006; received after revision 31 March 2006; accepted 11 May 2006 相似文献
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Evidence of undiscovered cell regulatory mechanisms: phosphoproteins and protein kinases in mitochondria 总被引:3,自引:0,他引:3
Thomson M 《Cellular and molecular life sciences : CMLS》2002,59(2):213-219
The finding that mitochondria contain substrates for protein kinases lead to the discovery that protein kinases are located
in the mitochondria of certain tissues and species. These include pyruvate dyhydrogenase kinase, branched-chain α-ketoacid dehydrogenase kinase, protein kinase A, protein kinase Cδ, stress-activated kinase and A-Raf as well as unidentified kinases. Recent evidence suggests that mitochondrial protein kinases
may be involved in physiological processes such as apoptosis and steroidogenesis. Additionally, the novel finding of low-molecular-weight
GTP-binding proteins in mitochondria suggests the possibility that these may interact with mitochondrial protein kinases to
regulate the activity of mitochondrial effector proteins. The fact that there are components of cellular regulatory systems
in mitochondria indicates the exciting possibility of undiscovered systems regulating mitochondrial physiology.
Received 19 June 2001; received after revision 7 August 2001; accepted 8 August 2001 相似文献
10.
The parvins 总被引:5,自引:0,他引:5
The parvins are a family of proteins involved in linking integrins and associated proteins with intracellular pathways that
regulate actin cytoskeletal dynamics and cell survival. Both α-parvin (PARVA) and β-parvin (PARVB) localize to focal adhesions
and function in cell adhesion, spreading, motility and survival through interactions with partners, such as integrin-linked
kinase (ILK), paxillin, α-actinin and testicular kinase 1. A complex of PARVA with ILK and the LIM protein PINCH-1 is critical
for cell survival in a variety of cells, including certain cancer cells, kidney podocytes and cardiac myocytes. While PARVA
inhibits the activities of Rac1 and testicular kinase 1 and cell spreading, PARVB binds αPIX and α-actinin, and can promote
cell spreading. In contrast to PARVA, PARVB inhibits ILK activity and reverses some of its oncogenic effects in cancer cells.
This review focuses on the structure and function of the parvins and some possible roles in human diseases.
Received 5 August 2005; received after revision 5 September 2005; accepted 22 September 2005 相似文献
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Sphingolipids in mammalian cell signalling 总被引:12,自引:0,他引:12
Sphingolipids and their metabolites, ceramide, sphingosine and sphingosine-1-phosphate, are involved in a variety of cellular
processes including differentiation, cellular senescence, apoptosis and proliferation. Ceramide is the main second messenger,
and is produced by sphingomyelinase-induced hydrolysis of sphingomyelin and by de novo synthesis. Many stimuli, e.g. growth
factors, cytokines, G protein-coupled receptor agonists and stress (UV irradiation) increase cellular ceramide levels. Sphingomyelin
in the plasma membrane is located primarily in the outer (extracellular) leaflet of the bilayer, whilst sphingomyelinases
are found at the inner (cytosolic) face and within lysosomes/endosomes. Such cellular compartmentalisation restricts the site
of ceramide production and subsequent interaction with target proteins. Glycosphingolipids and sphingomyelin together with
cholesterol are major components of specialised membrane microdomains known as lipid rafts, which are involved in receptor
aggregation and immune responses. Many signalling molecules, for example Src family tyrosine kinases and glycosylinositolphosphate-anchored
proteins, are associated with rafts, and disruption of these domains affects cellular responses such as apoptosis. Sphingosine
and sphingosine-1-phosphate derived from ceramide are also signalling molecules. In particular, sphingosine-1-phosphate is
involved in proliferation, differentiation and apoptosis. Sphingosine-1-phosphate can act both extracellularly through endothelial-differentiating
gene (EDG) family G protein-coupled receptors and intracellularly through direct interactions with target proteins. The importance
of sphingolipid signalling in cardiovascular development has been reinforced by recent reports implicating EDG receptors in
the regulation of embryonic cardiac and vascular morphogenesis.
Received 16 May 2001; received after revision 29 June 2001; accepted 3 July 2001 相似文献
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Signal regulation by family conspiracy 总被引:6,自引:0,他引:6
The signal regulating proteins (SIRPs) are a family of ubiquitously expressed transmembrane glycoproteins composed of two
subgroups: SIRPα and SIRPβ, containing more than ten members. SIRPα has been shown to inhibit signalling through a variety of receptors including receptor tyrosine kinases and cytokine receptors.
This function involves protein tyrosine kinases and is dependent on immunoreceptor tyrosine-based inhibition motifs which
recruit key protein tyrosine phosphatases to the membrane. Negative regulation by SIRPα may also involve its ligand, CD47, in a bi-directional signalling mechanism. The SIRPβ subtype has no cytoplasmic domain but instead associates with at least one other transmembrane protein (DAP-12, or KARAP).
DAP-12 possesses immunoreceptor tyrosine-based activation motifs within its cytoplasmic domain that are thought to link SIRPβ to activating machinery. SIRPα and SIRPβ thus have complementary roles in signal regulation and may conspire to tune the response to a stimulus.
Received 6 July 2000; revised 2 August 2000; accepted 5 August 2000 相似文献
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Sarramegn V Muller I Milon A Talmont F 《Cellular and molecular life sciences : CMLS》2006,63(10):1149-1164
G protein-coupled receptors (GPCRS) represent a class of integral membrane proteins involved in many biological processes
and pathologies. Fifty percent of all modern drugs and almost 25% of the top 200 bestselling drugs are estimated to target
GPCRs. Despite these crucial biological implications, very little is known, at atomic resolution, about the detailed molecular
mechanisms by which these membrane proteins are able to recognize their extra-cellular stimuli and transmit the associated
messages. Obviously, our understanding of GPCR functioning would be greatly facilitated by the availability of high-resolution
three-dimensional (3D) structural data. However, expression, solubilization and purification of these membrane proteins are
not easy to achieve, and at present, only one 3D structure has been determined, that of bovine rhodopsin. This review presents
and compares the different successful strategies which have been applied to solubilize and purify recombinant GPCRs in the
perspective of structural biology experiments.
Received 21 November 2005; received after revision 20 January 2006; accepted 2 February 2006
An erratum to this article is available at . 相似文献
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Danielle Kamato Muhamad Ashraf Rostam Rebekah Bernard Terrence J. Piva Nitin Mantri Daniel Guidone Wenhua Zheng Narin Osman Peter J. Little 《Cellular and molecular life sciences : CMLS》2015,72(4):799-808
G protein-coupled receptor (GPCR) signalling is mediated through transactivation-independent signalling pathways or the transactivation of protein tyrosine kinase receptors and the recently reported activation of the serine/threonine kinase receptors, most notably the transforming growth factor-β receptor family. Since the original observation of GPCR transactivation of protein tyrosine kinase receptors, there has been considerable work on the mechanism of transactivation and several pathways are prominent. These pathways include the “triple membrane bypass” pathway and the generation of reactive oxygen species. The recent recognition of GPCR transactivation of serine/threonine kinase receptors enormously broadens the GPCR signalling paradigm. It may be predicted that the transactivation of serine/threonine kinase receptors would have mechanistic similarities with transactivation of tyrosine kinase pathways; however, initial studies suggest that these two transactivation pathways are mechanistically distinct. Important questions are the relative importance of tyrosine and serine/threonine transactivation pathways, the contribution of transactivation to overall GPCR signalling, mechanisms of transactivation and the range of cell types in which this phenomenon occurs. The ultimate significance of transactivation-dependent signalling remains to be defined but it appears to be prominent and if so will represent a new cell signalling frontier. 相似文献
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Huntington’s disease: from huntingtin function and dysfunction to therapeutic strategies 总被引:3,自引:0,他引:3
Borrell-Pagès M Zala D Humbert S Saudou F 《Cellular and molecular life sciences : CMLS》2006,63(22):2642-2660
Huntington’s disease (HD) is a neurodegenerative disorder that usually starts in middle age and is characterized by involuntary
movements (chorea), personality changes and dementia, leading to death within 10–20 years. The defective gene in HD contains
a trinucleotide CAG repeat expansion within its coding region that expresses a polyglutamine repeat in the protein huntingtin.
Together with the characteristic formation of aggregates in HD, aberrant protein interactions and several post-translational
modifications affect huntingtin during disease progression and lead to the dysfunction and death of selective neurons in the
brains of patients. The exact molecular mechanisms by which mutant huntingtin induces cell death are not completely understood
but may involve the gain of new toxic functions and the loss of the beneficial properties of huntingtin. This review focuses
on the cellular functions in which huntingtin is involved and how a better understanding of pathogenic pathways can lead to
new therapeutic approaches.
Received 24 May 2006; received after revision 5 July 2006; accepted 23 August 2006 相似文献
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The function of apolipoproteins L 总被引:1,自引:0,他引:1
The function of the proteins of the apolipoprotein L (apoL) family is largely unknown. These proteins are classically thought
to be involved in lipid transport and metabolism, mainly due to the initial discovery that a secreted member of the family,
apoL-I, is associated with high-density lipoprotein particles. However, the other members of the family are believed to be
intracellular. The recent unravelling of the mechanism by which apoL-I kills African trypanosomes, as well as the increasing
evidence for modulation of apoL expression in various pathological processes, provides new insights about the functions of
these proteins. ApoLs share structural and functional similarities with proteins of the Bcl-2 family. Based on the activity
of apoL-I in trypanosomes and the comparison with Bcl-2 proteins, we propose that apoLs could function as ion channels of
intracellular membranes and be involved in mechanisms triggering programmed cell death.
Received 28 February 2006; received after revision 18 May 2006; accepted 2 June 2006 相似文献
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Immunophilins: for the love of proteins 总被引:1,自引:0,他引:1
Barik S 《Cellular and molecular life sciences : CMLS》2006,63(24):2889-2900
Immunophilins are chaperones that may also exhibit peptidylprolyl isomerase (PPIase) activity. This review summarizes our
knowledge of the two largest families of immunophilins, namely cyclophilin and FK506-binding protein, and a novel chimeric
dual-family immunophilin, named FK506- and cyclosporin-binding protein (FCBP). The larger members of each family are modular
in nature, consisting of multiple PPIase and/or protein-protein interaction domains. Despite the apparent difference in their
sequence and three-dimensional structure, the three families encode similar enzymatic and biological functions. Recent studies
have revealed that many immunophilins possess a chaperone function independent of PPIase activity. Knockout animal studies
have confirmed multiple essential roles of immunophilins in physiology and development. An immunophilin is indeed a natural
‘protein-philin’ (Greek ‘philin’ = friend) that interacts with proteins to guide their proper folding and assembly.
Received: 7 May 2006; received after revision 3 July 2006; accepted 24 August 2006 相似文献
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Phytanic acid is a branched-chain fatty acid that accumulates in a variety of metabolic disorders. High levels of phytanic
acid found in patients can exceed the millimolar range and lead to severe symptoms. Degradation of phytanic acid takes place
by α-oxidation inside the peroxisome. A deficiency of its breakdown, leading to elevated levels, can result from either a
general peroxisomal dysfunction or from a defect in one of the enzymes involved in α-oxidation. Research on Refsum disease,
belonging to the latter group of disorders and characterized by a deficiency of the first enzyme of α-oxidation, has extended
our knowledge of phytanic acid metabolism and pathology of the disease greatly over the past few decades. This review will
centre on this research on phytanic acid: its origin, the mechanism by which its α-oxidation takes place, its role in human
disease and the way it is produced from phytol.
Received 4 October 2005; received after revision 24 February 2006; accepted 26 April 2006 相似文献