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1.
The structure and function of heterotrimeric G protein subunits is known in considerable detail. Upon stimulation of a heptahelical
receptor by the appropriate agonists, the cognate G proteins undergo a cycle of activation and deactivation; the α-subunits and the βγ-dimers interact sequentially with several reaction partners (receptor, guanine nucleotides and effectors as well as regulatory
proteins) by exposing appropriate binding sites. For most of these domains, low molecular weight ligands have been identified
that either activate or inhibit signal transduction. These ligands include short peptides derived from receptors, G protein
subunits and effectors, mastoparan and related insect venoms, modified guanine nucleotides, suramin analogues and amphiphilic
cations. Because compounds that act on G proteins may be endowed with new forms of selectivity, we propose that G protein
subunits may therefore be considered as potential drug targets.
Received 18 September 1998; received after revision 6 November 1998; accepted 11 November 1998 相似文献
2.
D.M. Hunt S.E. Wilkie J.K. Bowmaker S. Poopalasundaram 《Cellular and molecular life sciences : CMLS》2001,58(11):1583-1598
Sensitivity to ultraviolet light (UV) is achieved by photoreceptors in the eye that contain a class of visual pigments maximally sensitive to light at wavelengths <400 nm. It is widespread in the animal kingdom where it is used for mate choice, communication and foraging for food. UV sensitivity is not, however, a constant feature of the visual system, and in many vertebrate species, the UV-sensitive (UVS) pigment is replaced by a violet-sensitive (VS) pigment with maximal sensitivity between 410 and 435 nm. The role of protonation of the Schiff base-chromophore linkage and the mechanism for tuning of pigments into the UV is discussed in detail. Amino acid sequence analysis of vertebrate VS/UVS pigments indicates that the ancestral pigment was UVS, with loss of UV sensitivity occurring separately in mammals, amphibia and birds, and subsequently regained by a single amino acid substitution in certain bird species. In contrast, no loss of UV sensitivity has occurred in the UVS pigments of insects. 相似文献
3.
Platelet-activating factor acetylhydrolases (PAF-AHs, EC 3.1.1.47) constitute a unique and biologically important family
of phospholipase A2s. They are related to neither the well-characterized secretory nor cytosolic PLA2s, and unlike them do not require Ca2+ for catalytic activity. The distinguishing property of PAF-AHs is their unique substrate specificity they act on the phospholipid
platelet-activating factor (PAF), and in some cases on proinflammatory polar phospholipids, from which they remove a short
acyl moiety – acetyl in the case of PAF – located at the sn-2 position. Because PAF is found both in the plasma and in the cytosol of many tissues, PAF-acetylhydrolases are equally widely
distributed in an animal organism. Recent crystallographic studies shed new light on the complex structure-function relationships
in PAF-AHs.
Received 15 September 1997; received after revision 23 February 1998; accepted 25 February 1998 相似文献
4.
H. Van Dael 《Cellular and molecular life sciences : CMLS》1998,54(11):1217-1230
Protein folding is an extremely active field of research where biology, chemistry, computer science and physics meet. Although
the study of protein-folding intermediates in general and equilibrium intermediates in particular has grown considerably in
recent years, many questions regarding the conformational state and the structural features of the various partially folded
intermediate states remain unanswered. Performing kinetic measurements on proteins that have had their structures modified
by site-directed mutagenesis, the so-called protein-engineering method, is an obvious way to gain fine structural information.
In the present review, this method has been applied to a variety of proteins belonging to the lysozyme/α-lactalbumin family. Besides recombinants obtained by point mutations of individual critical residues, chimeric proteins in
which whole structural elements (10 – 25 residues) from α-lactalbumin were inserted into a human lysozyme matrix are examined. The conformational properties of the equilibrium intermediate
states are discussed together with the structural characterization of the partially unfolded states encountered in the kinetic
folding pathway.
Received 28 May 1998; received after revision 6 July 1998; accepted 6 July 1998 相似文献
5.
H. Mueller 《Cellular and molecular life sciences : CMLS》1998,54(12):1291-1298
The discovery and cloning of the cytokine tumor necrosis factor α (TNF) gave rise to new hopes for a significant victory in the war against cancer. Preclinical in vitro studies in cell cultures
and in vivo studies in animal models demonstrated the antitumor capacities of TNF. Although clinical studies were largely
made possible by the availability of recombinant TNF, phase I and II clinical trials showed very quickly that the systemic
administration of TNF induced severe side effects mainly due to its pleiotropic action on immunocompetent cells. The clinical
manifestations of the side effects were similar to those observed during a severe infection and inflammation. Very recently,
lessons from these clinical studies yielded refined approaches whereby the toxicity of TNF is limited through local administration,
a combination with other therapeutic regimens and targeted gene therapy. These new approaches are slated for larger clinical
trials and in the near future might demonstrate the limited but powerful usefulness of TNF as an antineoplastic agent for
different types of cancer.
Received 7 September 1998; received after revision 15 October 1998; accepted 15 October 1998 相似文献
6.
Light perception in higher plants 总被引:4,自引:0,他引:4
Batschauer A 《Cellular and molecular life sciences : CMLS》1999,55(2):153-166
Photosynthetic plants depend on sunlight as their energy source. Thus, they need to detect the intensity, quality and direction
of this critical environmental factor and to respond properly by optimizing their growth and development. Perception of light
is accomplished by several photoreceptors including phytochromes, blue/ultraviolet (UV)-A and UV-B light photoreceptors. In
recent years, genetic, molecular genetic and cell biological approaches have significantly increased our knowledge about the
structure and function of the photoreceptors, and allowed the identification of several light signal transduction components.
Furthermore, this research led to fruitful interaction between different disciplines, such as molecular biology and ecology.
It is safe to assume that we can expect more milestones in this research field in the upcoming years. 相似文献
7.
Peptidyl-prolyl cis-trans isomerases, a superfamily of ubiquitous folding catalysts 总被引:21,自引:0,他引:21
Cyclosporine A therapy for prophylaxis against graft rejection revolutionized human organ transplantation. The immunosuppressant
drugs cyclosporin A (CsA), FK506 and rapamycin block T-cell activation by interfering with the signal transduction pathway.
The target proteins for CsA and FK506 were found to be cyclophilins and FK506-binding proteins, (FKBPs), respectively. They
are unrelated in primary sequence, although both are peptidyl-prolyl cis-trans isomerases catalyzing the interconversion of
peptidyl-prolyl imide bonds in peptide and protein substrates. However, the prolyl isomerase activity of these proteins is
not essential for their immunosuppressive effects. Instead, the specific surfaces of the cyclophilin-CsA and FKBP-FK506 complexes
mediate the immunosuppressive action. Moreover, the natural cellular functions of all but a few remain elusive. In some cases
it could be demonstrated that prolyl isomerization is the rate-limiting step in protein folding in vitro, but many knockout
mutants of single and multiple prolyl isomerases were viable with no detectable phenotype. Even though a direct requirement
for in vivo protein folding could not be demonstrated, some important natural substrates of the prolyl isomerases are now
known, and they demonstrate the great variety of prolyl isomerization functions in the living cell: (i) A human cyclophilin
binds to the Gag polyprotein of the human immunodeficiency virus-1 (HIV-1) virion and was found to be essential for infection
with HIV to occur, probably by removal of the virion coat. (ii) Together with heat shock protein (HSP) 90, a member of the
chaperone family, high molecular weight cyclophilins and FKBPs bind and activate steroid receptors. This example also demonstrates
that prolyl isomerases act together with other folding enzymes, for example the chaperones, and protein disulfide isomerases.
(iii) An FKBP was found to act as a modulator of an intracellular calcium release channel. (iv) Along with the cyclophilins
and FKBPs, a third class of prolyl isomerases exist, the parvulins. The human parvulin homologue Pin1 is a mitotic regulator
essential for the G2/M transition of the eukaryotic cell cycle. These findings place proline isomerases at the intersection
of protein folding, signal transduction, trafficking, assembly and cell cycle regulation.
Received 18 September 1998; received after revision 4 November 1998; accepted 23 November 1998 相似文献
8.
The molecular architecture of tight junctions has been a subject of extensive studies that have shown tight junctions to be
composed of many peripheral and integral membrane proteins. Claudins have been considered the main tight junction-forming
proteins; however, the role they play in a series of pathophysiological events, including human carcinoma development, is
only now beginning to be understood. Increasing evidence from in vitro and in vivo studies have identified the influence of claudins on tight junction structure and function, although claudins also participate
in cellular contexts other than tight junctions. The aim of this review is to summarize and discuss the conceptual framework
concerning claudins, focusing on the involvement of these proteins in epithelial cell polarity establishment, paracellular
transport control, signal transduction and tumorigenesis.
Received 5 July 2006; received after revision 29 August 2006; accepted 29 September 2006 相似文献
9.
Structural view of cadherin-mediated cell-cell adhesion 总被引:1,自引:0,他引:1
Following the multiplication of biochemical, biophysical and structural studies describing cadherin molecules and their interactions,
several ideas have emerged to explain the mechanisms of cadherin-mediated cell adhesion. Although different models were proposed
for cadherin interactions, a consensus has come forth considering lateral dimerization of cadherins as being a central component
of the cell-cell adhesion process. This review summarizes the recent development in structural studies of cadherins.
Received 14 September 1998; received after revision 14 November 1998; accepted 16 November 1998 相似文献
10.
Kirkpatrick DT 《Cellular and molecular life sciences : CMLS》1999,55(3):437-449
Numerous proteins are involved in the nucleotide excision repair (NER) and DNA mismatch repair (MMR) pathways. The function
and specificity of these proteins during the mitotic cell cycle has been actively investigated, in large part due to the involvement
of these systems in human diseases. In contrast, comparatively little is known about their functioning during meiosis. At
least three repair pathways operate during meiosis in the yeast Saccharomyces cerevisiae to repair mismatches that occur as a consequence of heteroduplex formation in recombination. The first pathway is similar
to the one acting during postreplicative mismatch repair in mitotically dividing cells, while two pathways are responsible
for the repair of large loops during meiosis, using proteins from MMR and NER systems. Some MMR proteins also help prevent
recombination between diverged sequences during meiosis, and act late in recombination to affect the resolution of crossovers.
This review will discuss the current status of DNA mismatch repair and nucleotide excision repair proteins during meiosis,
especially in the yeast S. cerevisiae.
Received 21 September 1998; received after revision 23 November 1998; accepted 23 November 1998 相似文献
11.
Molecular and structural effects of inverse agonistic mutations on signaling of the thyrotropin receptor – a basally active GPCR 总被引:1,自引:0,他引:1
Kleinau G Jaeschke H Mueller S Worth CL Paschke R Krause G 《Cellular and molecular life sciences : CMLS》2008,65(22):3664-3676
Several mutations that decrease the basal signaling activity of G-protein coupled receptors (GPCRs) with pathogenic implications
are known. Here we study the molecular mechanisms responsible for this phenotype and investigate how basal and further activated
receptor conformations are interrelated. In the basally active thyroid stimulating hormone receptor (TSHR) we combined spatially-distant
mutations with opposing effects on basal activity in double-mutations and characterized mutant basal and TSH induced signaling.
Mutations lowering basal activity always have a suppressive influence on TSH induced signaling and on constitutively activating
mutations (CAMs). Our results suggest that the conformation of a basally ‘silenced’ GPCR might impair its intrinsic capacity
for signaling compared to the wild-type. Striking differences in conformation and intramolecular interactions between TSHR
models built using the crystal structures of inactive rhodopsin and partially active opsin help illuminate the molecular details
underlying mutations decreasing basal activity.
G. Kleinau, H. Jaeschke: These two authors contributed equally to this work.
Received 31 July 2008; received after revision 12 September 2008; accepted 19 September 2008 相似文献
12.
E. Aloj Totàro F. A. Pisanti L. Hernàdi 《Cellular and molecular life sciences : CMLS》1984,40(4):382-383
Summary The yellow-brown pigment present in the sensory cells ofAplysia limacina was studied using light and electron microscopy. The ultrastructure, the high carotenoid content and the presence in neurons for which a turnover process has been hypothesized, indicate that these pigments are cytosomes, organelles involved in the production of energy in anaerobiosis.This investigation was conducted at the Zoological Station of Naples. 相似文献
13.
ERKs are the point of divergence of PKA and PKC activation by PTHrP in human skin fibroblasts 总被引:3,自引:0,他引:3
Fortino V Torricelli C Gardi C Valacchi G Rossi Paccani S Maioli E 《Cellular and molecular life sciences : CMLS》2002,59(12):2165-2171
Parathyroid hormone-related peptide (PTHrP) receptors, coupled to trimeric G proteins, operate in most target cells through
at least three different transduction routes: Gαs-mediated stimulation of adenylylcyclase (AC), Gαq-mediated activation of
phospholipase Cβ (PLC) and mitogen-activated protein kinase (MAPK) activation. In this study we investigated the relative
role of different pathways in human skin fibroblast prolifera-tion. Using chemical inhibitors and activators of signal transduction,
we demonstrated that: (i) AC/cAMP and PLC/1,4,5 inositol triphosphate/diacylglycerol second-messenger systems are simultaneously
activated following PTHrP binding to its receptors; (ii) the mitogenic response to PTHrP derives from a balance between two
counteracting pathways – an activating route mediated by protein kinase C (PKC) and an inhibitory route mediated by protein
kinase A (PKA); (iii) PTHrP mitogenic effects are largely dependent on MAPKs, whose activity can be modulate
d by both PKA and PKC. Our results indicate that MAPKs are common targets of both transduction routes and, at the same time,
their point of divergence in mediating PTHrP dual and opposite mitogenic effects.
Received 2 August 2002; received after revision 10 September 2002; accepted 18 October 2002
RID="*"
ID="*"Corresponding author. 相似文献
14.
Gineitis A Treigyte G Savickiene J Shanbhag VP Stigbrand T 《Cellular and molecular life sciences : CMLS》1999,55(2):317-326
The two-dimensional electrophoretic patterns of nuclear proteins and their tyrosine phosphorylation were compared for HL-60
cells before and after differentiation induction to granulocytes by dimethyl sulfoxide, all-trans retinoic acid and N
6,O
2-dibutyryl adenosine 3′5′-cyclic monophosphate. Regardless of the inducer used, some nuclear proteins, which are tyrosine-phosphorylated
in proliferating HL-60 cells, undergo gradual dephosphorylation 12–72 h after induction of differentiation, followed by drastic
dephosphorylation during maturation to granulocytes. At least 13 nuclear proteins with a molecular mass of 35–110 kDa are
dephosphorylated, and 6 nuclear proteins undergo tyrosine phosphorylation. Analysis of the nuclear proteins differentially
extracted by salt and detergents indicates that changes in their tyrosine phosphorylation during the maturation stage of differentiating
granulocytes occur mainly in proteins which are abundant in nucleoplasm, chromatin and residual nuclear structures. The abundance
of these proteins, residing in the nuclear structures, and their long-term modification in phosphorylation during the maturation
stages of differentiation strongly suggest that tyrosine phosphorylation of these proteins is involved in reorganization of
the differentiating cell nucleus.
Received 21 September 1998; received after revision 24 November 1998; accepted 3 December 1998 相似文献
15.
Frings S 《Cellular and molecular life sciences : CMLS》2001,58(4):510-519
When odorants bind to the sensory cilia of olfactory sensory neurons, the cells respond with an electrical output signal,
typically a short train of action potentials. This review describes the present state of knowledge about the olfactory signal
transduction process. In the last decade, a set of transduction molecules has been identified which help to explain many aspects
of the sensory response. Odor-induced second-messenger production, activation of transduction channels, the central role of
the ciliary Ca2+ concentration, as well as mechanisms that mediate adaptation, are all qualitatively understood on the basis of a consistent
scheme for chemoelectrical transduction. This scheme, although necessarily incomplete, can serve as a working model for further
experimentation which may reveal kinetical aspects of signal transduction processes in olfactory sensory neurons. 相似文献
16.
K. Arikawa Y. Morikawa T. Suzuki E. Eguchi 《Cellular and molecular life sciences : CMLS》1988,44(3):219-220
Summary Under conditions of constant darkness, rhabdom volume and the amount of visual pigment chromophore show circadian changes in the compound eye of the crabHemigrapsus sanguineus. The present results indicate that an intrinsic circadian biological clock is involved in the control of the changes. 相似文献
17.
Davies WI Zheng L Hughes S Tamai TK Turton M Halford S Foster RG Whitmore D Hankins MW 《Cellular and molecular life sciences : CMLS》2011,68(24):4115-4132
Melanopsin (OPN4) is an opsin photopigment that, in mammals, confers photosensitivity to retinal ganglion cells and regulates
circadian entrainment and pupil constriction. In non-mammalian species, two forms of opn4 exist, and are classified into mammalian-like (m) and non-mammalian-like (x) clades. However, far less is understood of the function of this photopigment family. Here we identify in zebrafish five
melanopsins (opn4m-1, opn4m-2, opn4m-3, opn4x-1 and opn4x-2), each encoding a full-length opsin G protein. All five genes are expressed in the adult retina in a largely non-overlapping
pattern, as revealed by RNA in situ hybridisation and immunocytochemistry, with at least one melanopsin form present in all
neuronal cell types, including cone photoreceptors. This raises the possibility that the teleost retina is globally light
sensitive. Electrophysiological and spectrophotometric studies demonstrate that all five zebrafish melanopsins encode a functional
photopigment with peak spectral sensitivities that range from 470 to 484 nm, with opn4m-1 and opn4m-3 displaying invertebrate-like
bistability, where the retinal chromophore interchanges between cis- and trans-isomers in a light-dependent manner and remains within the opsin binding pocket. In contrast, opn4m-2, opn4x-1 and opn4x-2
are monostable and function more like classical vertebrate-like photopigments, where the chromophore is converted from 11-cis to all-trans retinal upon absorption of a photon, hydrolysed and exits from the binding pocket of the opsin. It is thought that all melanopsins
exhibit an invertebrate-like bistability biochemistry. Our novel findings, however, reveal the presence of both invertebrate-like
and vertebrate-like forms of melanopsin in the teleost retina, and indicate that photopigment bistability is not a universal
property of the melanopsin family. The functional diversity of these teleost melanopsins, together with their widespread expression
pattern within the retina, suggests that melanopsins confer global photosensitivity to the teleost retina and might allow
for direct “fine-tuning” of retinal circuitry and physiology in the dynamic light environments found in aquatic habitats. 相似文献
18.
Modulation of signal transduction through the cellular prion protein is linked to its incorporation in lipid rafts 总被引:3,自引:0,他引:3
Hugel B Martínez MC Kunzelmann C Blättler T Aguzzi A Freyssinet JM 《Cellular and molecular life sciences : CMLS》2004,61(23):2998-3007
Because expressed at a significant level at the membrane of human T cells, we made the hypothesis that the cellular prion protein (PrPc) could behave as a receptor, and be responsible for signal transduction. PrPc engagement by specific antibodies was observed to induce an increase in cytosolic calcium concentration and led to enhanced activity of Src protein tyrosine kinases. Antibodies to CD4 and CD59 did not influence calcium fluxes or signaling. The effect was maximal after the formation of a network involving avidin and biotinylated antibody to PrPc and was inhibited after raft disruption. PrPc localization was not restricted to rafts in resting cells but engagement was a prerequisite for signaling induction, with concomitant PrPc recruitment into rafts. These results suggest a role for PrPc in signaling pathways, and show that lateral redistribution of the protein into rafts is important for subsequent signal transduction.Received 22 July 2004; received after revision 10 September 2004; accepted 7 October 2004 相似文献
19.
Structure, function and evolution of antifreeze proteins 总被引:16,自引:0,他引:16
Antifreeze proteins bind to ice crystals and modify their growth. These proteins show great diversity in structure, and they
have been found in a variety of organisms. The ice-binding mechanisms of antifreeze proteins are not completely understood.
Recent findings on the evolution of antifreeze proteins and on their structures and mechanisms of action have provided new
understanding of these proteins in different contexts. The purpose of this review is to present the developments in contrasting
research areas and unite them in order to gain further insight into the structure and function of the antifreeze proteins.
Received 2 September 1998; received after revision 21 October 1998; accepted 2 November 1998 相似文献
20.
F. E. Weber J. H. Dyer F. López García M. Werder T. Szyperski K. Wüthrich H. Hauser 《Cellular and molecular life sciences : CMLS》1998,54(7):751-759
The preform of the rabbit sterol carrier protein 2 (pre-rSCP2) was cloned, the uniformly 15N-labelled protein expressed in Escherichia coli and studied by three-dimensional 15N-resolved nuclear magnetic resonance spectroscopy. In spite of its low solubility in aqueous solution of only ∼0.3 mM, sequential
15N and 1H backbone resonance assignments were obtained for 105 out of the 143 residues. From comparison of the sequential and medium-range
nuclear Overhauser effects (NOEs) in the two proteins, all regular secondary structures previously determined in mature human
SCP2 (hSCP2) [Szyperski et al. (1993) FEBS Lett. 335: 18–26] were also identified in pre-rSCP2. Near-identity of the backbone 15N and 1H chemical shifts and 1 : 1 correspondence of 24 long-range NOEs to backbone amide groups in the two proteins show that the
residues 21 – 143 adopt the same globular fold in pre-rSCP2 and mature hSCP2. The N-terminal 20-residue leader peptide of pre-rSCP2 is flexibly disordered in solution and does not observably affect the conformation of the polypeptide segment 21 – 143.
Received 11 May 1998; accepted 15 May 1998 相似文献