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1.
Integrins and cardiovascular disease 总被引:2,自引:0,他引:2
Cardiovascular diseases involve abnormal cell-cell interactions leading to the development of atherosclerotic plaque, which
when ruptured causes massive platelet activation and thrombus formation. Parts of a loose thrombus may detach to form an embolus,
blocking circulation at a more distant point. The integrins are a family of adhesive cell receptors interacting with adhesive
proteins or with counterreceptors on other cells. There is now solid evidence that the major integrin on platelets, the fibrinogen
receptor α
IIb
β
3 , has an important role in several aspects of cardiovascular diseases and that its regulated inhibition leads to a reduction
in incidence and mortality due to these disorders. The development of α
IIb
β
3 inhibitors is an important strategy of many pharmaceutical companies which foresee a large market for the treatment of acute
conditions in surgery, the symptoms of chronic conditions and, it is hoped, maybe even the successful prophylaxis of these
conditions. Although all the associated problems have not been solved, the undoubted improvements in patient care resulting
from the first of these treatments in the clinic have stimulated further research on the role of integrins on other vascular
cells in these processes and in the search for new inhibitors. Both the development of specific inhibitors and of mice with
specific integrin subunit genes ablated have contributed to a better understanding of the function of integrins in development
of the cardiovascular system. 相似文献
2.
M. Capdevila N. Cols N. Romero-Isart R. Gonzàlez-Duarte S. Atrian P. Gonzàlez-Duarte 《Cellular and molecular life sciences : CMLS》1997,53(8):681-688
Genetic engineering, coupled with spectro scopic analyses, has enabled the metal binding proper ties of the α and β subunits of mouse metallothionein 1 (MT) to be characterized. A heterologous expression system in E.coli has led to high yields of their pure zinc-complexed forms. The cadmium(II) binding properties of recombinant Zn4-αMT and Zn3-βMT have been studied by electronic absorption and circular dichroism. The former binds Cd(II) identically to α fragments obtained from mammalian organs, showing that the recombinant polypeptide behaves like the na tive protein. Titration
of Zn3-βMT with CdCl2 results in the formation of Cd3-βMT. The addition of excess Cd(II) leads to Cd4-βMT which, with the extra loading of Cd(II), unravels to give rise isodichroically to Cd9-βMT. The effect of cadmium-displaced Zn(II) ions and excess Cd(II) above the full metal occupancy of three has been studied
using Chelex-100. The Cd3-βMT species is stable in the presence of this strong metal-chelating agent.
Received 20 May 1997; received after revision 7 July 1997; accepted 9 July 1997 相似文献
3.
The human hair follicle is composed of different concentric compartments, which reflect different programmes of differentiation.
Using monoclonal antibodies against α2β1 and α3β1 integrins we demonstrated a shift in their expression, from a basolateral distribution in the basal cells of the lower outer
root sheath, to an apicolateral expression in the upper outer root sheath, as in epidermis. This shift takes place in a transition
zone, localized to the midpart of the follicle. The distinct basolateral distribution of α2β1 and α3β1 integrins in the lower portion of the outer root sheath coincides with the presence of basal cell protrusions and is probably
linked to the presence of the vitreous membrane which surrounds the bottom part of the anagen human hair follicle. Moreover,
we showed that the expression of α6β4 integrin is discontinuous along the hair follicle and coincides with that of laminin 5. Together these results establish
that within a given compartment – namely the outer root sheath – several domains can be clearly identified, which probably
reflect the onset of successive differentiation pathways along the hair follicle.
Received 17 January 1997; received after revision 18 February 1997; accepted 24 February 1997 相似文献
4.
Sánchez-Margalet V González-Yanes C Santos-Alvarez J Najib S 《Cellular and molecular life sciences : CMLS》1999,55(1):142-147
Insulin action is initiated by binding to its cognate receptor, which then triggers multiple cellular responses by activating
different signaling pathways. There is evidence that insulin receptor signaling may involve G protein activation in different
target cells. We have studied the activation of G proteins in rat hepatoma (HTC) cells. We found that insulin stimulated binding
of guanosine 5′-O-(3-thiotriphosphate) (GTP-γ-35S) to plasma membrane proteins of HTC cells, in a dose-dependent manner. This effect was completely blocked by pertussis toxin
treatment of the membranes, suggesting the involvement of G proteins of the Gα
i/Gα
o family. The expression of these Gα proteins was checked by Western blotting. Next, we used blocking antibodies to sort out the specific Gα protein activated by insulin stimulation. Anti-Gα
il,2 antibodies completely prevented insulin-stimulated GTP binding, whereas anti-Gα
o,i3 did not modify this effect of insulin on GTP binding. Moreover, we found physical association of the insulin receptor with
Gα
i1,2 by copurification studies. These results further support the involvement of a pertussis toxin-sensitive G protein in insulin
receptor signaling and provides some evidence of specific association and activation of Gα
i1,2 protein by insulin. These findings suggest that Gα
i1,2 proteins might be involved in insulin action.
Received 23 September 1998; received after revision 23 November 1998; accepted 25 November 1998 相似文献
5.
The prolyl oligopeptidase family 总被引:6,自引:0,他引:6
Polgár L 《Cellular and molecular life sciences : CMLS》2002,59(2):349-362
A group of serine peptidases, the prolyl oligopeptidase family, cannot hydrolyze peptides containing more than about 30 residues.
This group is unrelated to the classical trypsin and subtilisin families, and includes dipeptidyl peptidase IV, acylaminoacyl
peptidase and oligopeptidase B, in addition to the prototype prolyl oligopeptidase. The recent crystal structure determination
of prolyl oligopeptidase (80 kDa) has shown that the enzyme contains a peptidase domain with an α/β hydrolase fold, and its catalytic triad is covered by the central tunnel of an unusual seven-bladed β-propeller. This domain operates as a gating filter, excluding large, structured peptides from the active site. The binding
mode of substrates and the catalytic mechanism differ from that of the classical serine peptidases in several features. The
members of the family are important targets of drug design. Prolyl oligopeptidase is involved in amnesia, depression and blood
pressure control, dipeptidyl peptidase IV in type 2 diabetes and oligopeptidase B in trypanosomiasis.
Received 8 August 2001; received after revision 19 September 2001; accepted 21 September 2001 相似文献
6.
Prosperi-Meys C Wouters J Galleni M Lamotte-Brasseur J 《Cellular and molecular life sciences : CMLS》2001,58(14):2136-2143
Increased resistance to β-lactam antibiotics is mainly due to β-lactamases whose production by pathogenic bacteria makes their broad activity spectrum
especially frightening. X-ray structures of several zinc β-lactamases have revealed the coordination of the two metal ions, but their mode of action remains unclear. Geometry optimisation
of stable complexes along the reaction pathway of benzylpenicillin hydrolysis highlighted a proton shuttle occurring from
D120 of the Bacillus cereus β-lactamase to the β-lactam nitrogen via Zn2 which is central to the network. First, the Zn1 ion has a structural role maintaining Zn-bound waters,
WAT1 and WAT2, either directly or through the Zn1 tetrahedrally coordinated histidine ligands. The Zn2 ion has a more catalytic
role, stabilising the tetrahedral intermediate, accepting the β-lactam nitrogen atom as a ligand. The role of Zn2 and the flexibility in the coordination geometry of both Zn ions is of
crucial importance for catalysis.
Received 14 August 2001; received after revision 19 October 2001; accepted 30 October 2001 相似文献
7.
Bromelain: biochemistry, pharmacology and medical use 总被引:10,自引:0,他引:10
Maurer HR 《Cellular and molecular life sciences : CMLS》2001,58(9):1234-1245
Bromelain is a crude extract from the pineapple that contains, among other components, various closely related proteinases,
demonstrating, in vitro and in vivo, antiedematous, antiinflammatory, antithrombotic and fibrinolytic activities. The active
factors involved are biochemically characterized only in part. Due to its efficacy after oral administration, its safety and
lack of undesired side effects, bromelain has earned growing acceptance and compliance among patients as a phytotherapeutical
drug. A wide range of therapeutic benefits has been claimed for bromelain, such as reversible inhibition of platelet aggregation,
angina pectoris, bronchitis, sinusitis, surgical traumas, thrombophlebitis, pyelonephritis and enhanced absorption of drugs,
particularly of antibiotics. Biochemical experiments indicate that these pharmacological properties depend on the proteolytic
activity only partly, suggesting the presence of nonprotein factors in bromelain. Recent results from preclinical and pharmacological
studies recommend bromelain as an orally given drug for complementary tumor therapy: bromelain acts as an immunomodulator
by raising the impaired immunocytotoxicity of monocytes against tumor cells from patients and by inducing the production of
distinct cytokines such as tumor necrosis factor-α, interleukin (Il)-1β, Il-6, and Il-8. In a recent clinical study with mammary tumor patients, these findings could be partially confirmed. Especially
promising are reports on animal experiments claiming an antimetastatic efficacy and inhibition of metastasis-associated platelet
aggregation as well as inhibition of growth and invasiveness of tumor cells. Apparently, the antiinvasive activity does not
depend on the proteolytic activity. This is also true for bromelain effects on the modulation of immune functions, its potential
to eliminate burn debris and to accelerate wound healing. Whether bromelain will gain wide acceptance as a drug that inhibits
platelet aggregation, is antimetastatic and facilitates skin debridement, among other indications, will be determined by further
clinical trials. The claim that bromelain cannot be effective after oral administration is definitely refuted at this time.
Received 25 August 2000; received after revision 29 March 2001; accepted 30 March 2001 相似文献
8.
Biased binding of class IA phosphatidyl inositol 3-kinase subunits to inducible costimulator (CD278)
Acosta YY Zafra MP Ojeda G Bernardone IS Dianzani U Portolés P Rojo JM 《Cellular and molecular life sciences : CMLS》2011,68(18):3065-3079
To better understand T lymphocyte costimulation by inducible costimulator (ICOS; H4; CD278), we analyzed proteins binding
to ICOS peptides phosphorylated at the Y191MFM motif. Phosphorylated ICOS binds class IA phosphatidyl inositol 3-kinase (PI3-K) p85α, p50-55α and p85β regulatory subunits
and p110α, p110δ and p110β catalytic subunits. Intriguingly, T cells expressed high levels of both p110α or p110δ catalytic
subunits, yet ICOS peptides, cell surface ICOS or PI3-kinase class IA regulatory subunits preferentially coprecipitated p110α
catalytic subunits. Silencing p110α or p110δ partially inhibited Akt/PKB activation induced by anti-CD3 plus anti-ICOS antibodies.
However, silencing p110α enhanced and silencing p110δ inhibited Erk activation. Both p110α- and p110δ-specific inhibitors
blocked cytokine secretion induced by TCR/CD3 activation with or without ICOS costimulus, but only p110α inhibitors blocked
ICOS-induced cell elongation. Thus, p110α and p110δ are essential to optimal T cell activation, but their abundance and activity
differentially tune up distinct ICOS signaling pathways. 相似文献
9.
Bataille D Héron L Virsolvy A Peyrollier K LeCam A Gros L Blache P 《Cellular and molecular life sciences : CMLS》1999,56(1-2):78-84
ATP-dependent potassium (KATP) channels occupy a key position in the control of insulin release from the pancreatic β cell since they couple cell polarity
to metabolism. These channels close when more ATP is produced via glucose metabolism. They are also controlled by sulfonylureas,
a class of drugs used in type 2 diabetic patients for triggering insulin secretion from β cells that have lost part of their
sensitivity to glucose. We have demonstrated the existence of endogenous counterparts to sulfonylureas which we have called
‘endosulfines.’ In this review, we describe the discovery, isolation, cloning, and biological features of the high-molecular-mass
form, α-endosulfine, and discuss its possible role in the physiology of the β cell as well as in pathology.
Received 1 February 1999; received after revision 26 March 1999; accepted 26 March 1999 相似文献
10.
Ligand recognition by the I domain-containing integrins 总被引:11,自引:0,他引:11
Seven of the integrin α subunits described to date, α
1 , α
2 , α
L , α
X , α
d , α
M and α
E , contain a highly conserved I (or A) domain of approximately 200 amino acid residues inserted near the amino-terminus of
the subunit. As the result of a variety of independent experimental approaches, a large body of data has recently accumulated
that indicates that the I domains are independent, autonomously folding domains capable of directly binding ligands that play
a necessary and important role in ligand binding by the intact integrins. Recent crystallographic studies have elucidated
the structures of recombinant α
M and α
L I domains and also delineated a novel divalent cation-binding motif within the I domains (metal ion-dependent adhesion site,
MIDAS) that appears to mediate the divalent cation binding of the I domains and the I domain-containing integrins to their
ligands. 相似文献
11.
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
12.
Toniolo C Crisma M Formaggio F Peggion C Epand RF Epand RM 《Cellular and molecular life sciences : CMLS》2001,58(9):1179-1188
Lipopeptaibols are members of a novel group of naturally occurring, short peptides with antimicrobial activity, characterized
by a lipophilic acyl chain at the N-terminus, a high content of the turn/helix forming α-aminoisobutyric acid and a 1,2-amino alcohol at the C-terminus. The amino acid sequences range from 6 to 10 residues and
the fatty acyl moieties from 8 to 15 carbon atoms. The peptide portion of lipopeptaibols can be shorter than those of the
nonlipidated peptaibols that range from 10 to 19 amino acid residues. The longest peptides fold into a mixed 310/α helix, whereas the shortest peptides tend to adopt a β-turn/sheet structure. Using solution methodologies, a series of analogues of trichogin GA IV was synthesized which allowed
determination of the minimal lipid chain and peptide main-chain lengths for the onset of membrane activity and exploitation
of a number of spectroscopic techniques aimed at determining its preferred conformation under a variety of conditions and
investigating in detail its mode of interaction with, and its effect on, the phospholipid membranes.
Received 26 January 2001; received after revision 7 March 2001; accepted 15 March 2001 相似文献
13.
One of the central elements of excitation-contraction coupling, the voltage-sensing dihydropyridine receptor, is believed
to exist as a high-molecular-mass complex in the triad junction. Although freeze-fracture electron microscopical analysis
suggests a tetrad complex, no direct biochemical evidence exists demonstrating the actual size of the native membrane complex.
Using a combination of various two-dimensional gel electrophoresis techniques, we show here that the principal α
1-subunit of the dihydropyridine receptor and its auxiliary α
2-subunit form a triad complex of approximately 2800 kDa under native conditions. Established Ca2+-ATPase tetramers and calsequestrin monomers were employed for the internal standardization of the gel systems used. Thus,
the large voltage-sensing complex appears to be tightly associated, since it does not disintegrate during subcellular fractionation
and native electrophoresis procedures. Our findings support the cell biological hypothesis that native dihydropyridine receptor
units form a tetrad structure within the transverse tubules.
Received 10 October 2000; revised 28 November 2000; accepted 4 January 2001 相似文献
14.
James R. Ketudat Cairns Asim Esen 《Cellular and molecular life sciences : CMLS》2010,67(20):3389-3405
β-Glucosidases (3.2.1.21) are found in all domains of living organisms, where they play essential roles in the removal of
nonreducing terminal glucosyl residues from saccharides and glycosides. β-Glucosidases function in glycolipid and exogenous
glycoside metabolism in animals, defense, cell wall lignification, cell wall β-glucan turnover, phytohormone activation, and
release of aromatic compounds in plants, and biomass conversion in microorganisms. These functions lead to many agricultural
and industrial applications. β-Glucosidases have been classified into glycoside hydrolase (GH) families GH1, GH3, GH5, GH9,
and GH30, based on their amino acid sequences, while other β-glucosidases remain to be classified. The GH1, GH5, and GH30
β-glucosidases fall in GH Clan A, which consists of proteins with (β/α)8-barrel structures. In contrast, the active site of GH3 enzymes comprises two domains, while GH9 enzymes have (α/α)6 barrel structures. The mechanism by which GH1 enzymes recognize and hydrolyze substrates with different specificities remains
an area of intense study. 相似文献
15.
Diego-García E Abdel-Mottaleb Y Schwartz EF de la Vega RC Tytgat J Possani LD 《Cellular and molecular life sciences : CMLS》2008,65(1):187-200
Among the scorpion venom components whose function are poorly known or even show contrasting pharmacological results are those
called “orphan peptides”. The most widely distributed are named β-KTx or scorpine-like peptides. They contain three disulfide
bridges with two recognizable domains: a freely moving N-terminal amino acid sequence and a tightly folded C-terminal region
with a cysteine-stabilized α/β (CS-αβ) motif. Four such peptides and three cloned genes are reported here. They were assayed
for their cytolytic, antimicrobial and K
+ channel-blocking activities. Two main characteristics were found: the existence of an unusual structural and functional diversity,
whereby the full-length peptide can lyse cells or kill microorganisms, and a C-terminal domain containing the CS-αβ motif
that can block K
+ channels. Furthermore, sequence analyses and phylogenetic reconstructions are used to discuss the evolution of this type
of peptide and to highlight the versatility of the CS-αβ structures.
Received 13 August 2007; received after revision 30 October 2007; accepted 2 November 2007 相似文献
16.
4-Hydroxynonenal-modified amyloid-beta peptide inhibits the proteasome: possible importance in Alzheimer's disease 总被引:3,自引:0,他引:3
Shringarpure R Grune T Sitte N Davies KJ 《Cellular and molecular life sciences : CMLS》2000,57(12):1802-1809
The amyloid β-peptide (Aβ) is a 4-kDa species derived from the amyloid precursor protein, which accumulates in the brains of patients with Alzheimer’s
disease. Although we lack full understanding of the etiology and pathogenesis of selective neuron death, considerable data
do imply roles for both the toxic Aβ and increased oxidative stress. Another significant observation is the accumulation of abnormal, ubiquitin-conjugated proteins
in affected neurons, suggesting dysfunction of the proteasome proteolytic system in these cells. Recent reports have indicated
that Aβ can bind and inhibit the proteasome, the major cytoslic protease for degrading damaged and ubiquitin-conjugated proteins.
Earlier results from our laboratory showed that moderately oxidized proteins are preferentially recognized and degraded by
the proteasome; however, severely oxidized proteins cannot be easily degraded and, instead, inhibit the proteasome. We hypothesized
that oxidatively modified Aβ might have a stronger (or weaker) inhibitory effect on the proteasome than does native Aβ. We therefore also investigated the proteasome inhibitory action of Aβ
1–40 (a peptide comprising the first 40 residues of Aβ) modified by the intracellular oxidant hydrogen peroxide, and by the lipid peroxidation product 4-hydroxynonenal (HNE). H2O2 modification of Aβ
1–40 generates a progressively poorer inhibitor of the purified human 20S proteasome. In contrast, HNE modification of Aβ
1–40 generates a progressively more selective and efficient inhibitor of the degradation of fluorogenic peptides and oxidized
protein substrates by human 20S proteasome. This interaction may contribute to certain pathological manifestations of Alzheimer’s
disease
Received 26 September 2000; accepted 26 September 2000 相似文献
17.
R.E. Williamson J.E. Burn C.H. Hocart 《Cellular and molecular life sciences : CMLS》2001,58(10):1475-1490
Cellulose microfibrils containing crystalline β-1,4-glucan provide the major structural framework in higher-plant cell walls. Genetic analyses of Arabidopsis thaliana now link specific genes to plant cellulose production just as was achieved some years earlier with bacteria. Cellulose-deficient
mutants have defects in several members of one family within a complex glycosyltransferase superfamily and in one member of
a small family of membrane-bound endo-1,4-β-glucanases. The mutants also accumulate a readily extractable β-1,4-glucan that has short chains which, in at least one case, are lipid linked. Cellulose could be made by direct extension
of the glucan chain by the glycosyltransferase or, as the mutant suggests, by an indirect route which makes lipid-linked oligosaccharides.
Models discussed incorporate the known enzymes and lipo-glucan and raise the possibility that different CesA glycosyltransferases
may catalyse different steps.
Received 5 January 2001; received after revision 25 April 2001; accepted 25 April 2001 相似文献
18.
E. Katchalski-Katzir 《Cellular and molecular life sciences : CMLS》1997,53(10):780-789
During the 1950s, linear and multichain poly-α-amino acids were synthesized by polymerization of the corresponding N-carboxyamino acid anhydrides in solution in the presence
of suitable catalysts. The resulting homo- and heteropolymers have since been widely employed as simple protein models. Under
appropriate conditions, poly-α-amino acids, in the solid state and in solution, were found to acquire conformations of an α-helix and of β-parallel and antiparallel pleated sheets, or to exist as random coils. Their use in experimental and theoretical investigations
of helix-coil transitions helped to shed new light on the mechanisms involved in protein denaturation. Conformational fluctuations
of peptides in solution were analysed theoretically and studied experimentally by nonradiative energy-transfer techniques.
Poly-α-amino acids played an important role in the deciphering of the genetic code. In addition, analysis of the antigenicity of
poly-α-amino acids led to the elucidation of the factors determining the antigenicity of proteins and peptides. The synthetic procedures
developed made possible the preparation of immobilized enzymes which were shown to be of considerable use as heterogeneous
biocatalysts in the chemical and pharmaceutical industry. Interest in the biological and physicochemical characteristics of
poly-α-amino acids was recently renewed because of the reported novel findings that some copolymers of amino acids are effective
as drugs in multiple sclerosis, and that glutamine repeats and reiteration of other amino acids occur in inherited neurodegenerative
diseases. 相似文献
19.
Lau LF 《Cellular and molecular life sciences : CMLS》2011,68(19):3149-3163
CCN1 (CYR61) is a dynamically expressed, multifunctional matricellular protein that plays essential roles in cardiovascular
development during embryogenesis, and regulates inflammation, wound healing and fibrogenesis in the adult. Aberrant CCN1 expression
is associated with myriad pathologies, including various cancers and diseases associated with chronic inflammation. CCN1 promotes
diverse and sometimes opposing cellular responses, which can be ascribed, as least in part, to disparate activities mediated
through its direct binding to distinct integrins in different cell types and contexts. Accordingly, CCN1 promotes cell proliferation,
survival and angiogenesis by binding to integrin αvβ3, and induces apoptosis and senescence through integrin α6β1 and heparan sulfate proteoglycans. The ability of CCN1 to trigger the accumulation of a robust and sustained level of reactive
oxygen species underlies some of its unique activities as a matrix cell-adhesion molecule. Emerging studies suggest that CCN1
might be useful as a biomarker or therapeutic target in certain diseases. 相似文献
20.
Fontana M Pinnen F Lucente G Pecci L 《Cellular and molecular life sciences : CMLS》2002,59(3):546-551
The naturally occurring dipeptides carnosine and anserine have been proposed to act as antioxidants in vivo. We investigated
whether these compounds can act as protective agents able to counteract peroxynitrite-dependent reactions. The results showed
that the dipeptides efficiently protect tyrosine against nitration, α1-antiproteinase against inactivation and human low-density lipoprotein against modification by peroxynitrite. Carnosine exerts
its protective effect at concentrations similar to those found in human tissues. In addition, some synthetic pseudodipeptides,
stucturally related to carnosine but stable to hydrolytic enzymes, possess protective properties against peroxynitrite-dependent
damage similar to the natural dipeptides. These pseudodipeptides may represent stable mimics of the biologically active carnosine
suitable for pharmacological applications.
Received 9 November 2001; received after revision 19 December 2001; accepted 15 January 2002 相似文献