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At least 19 recordsLinked to original sources

PubMed2004

The crystal structure of annexin A8 is similar to that of annexin A3.

Annexin A8 is a relatively infrequent and poorly studied member of this large family of calcium-binding and membrane-binding proteins. It is, however, associated with a specific disease, acute promyelocytic leukemia. We have solved its three-dimensional structure, which includes a moderately long and intact N terminus. The structure is closest to that of annexin A3 and highlights several important regions of inherent flexibility in the annexin molecule. The N terminus resembles that of annexin A3, as it lies along the concave surface of the molecule and inserts partially into the hydrophilic channel in its centre. Since both annexins A3 and A8 are expressed in promyelocytic cells during their differentiation, the similarity in their structures might suggest a functional relationship.

Annexin A3↗

PubMed2005

Expression of annexin A3 in primary cultured parenchymal rat hepatocytes and inhibition of DNA synthesis by suppression of annexin A3 expression using RNA interference.

Annexin A3 is a member of the lipocortin/annexin family, which binds to phospholipids and membranes in a Ca(2+)-dependent manner. Although annexin A3 has various functions in vitro, its cellular significance is completely unknown. Annexin A3 is not found in rat liver in vivo. In the present study, we investigated the expression of annexin A3 in primary cultured parenchymal rat hepatocytes. Annexin A3 protein was detected in 48-h, but not 2.5-h, cultured hepatocytes using Western blot analysis. The annexin A3 level further increased after an additional 24 h of culture. Annexin A3 mRNA was not detected in 2.5-h cultured hepatocytes but was detected 22 h after the start of culture by RT-PCR analysis, reaching a maximum value after 48 h of culture. To define the role of Annexin A3 in DNA synthesis, RNA interference was used to reduce annexin III gene expression in hepatocytes. The transfection of small interfering RNAs targeting annexin A3 in the hepatocytes reduced the corresponding mRNA and protein expression by approximately 80% and more than 90%, respectively, at 24 h after transfection. In the annexin A3 small interfering RNAs-transfected cells, DNA synthesis, as assessed by [3H]thymidine incorporation, decreased by approximately 70% not only in the control cultures, but also in the hepatocyte growth factor- or epidermal growth factor-treated cells. These findings show that annexin A3 is expressed in primary cultured parenchymal rat hepatocytes and that the suppression of annexin A3 expression using RNA interference inhibits DNA synthesis.

Animals↗

PubMed2007

Differential radioactive quantification of protein abundance ratios between benign and malignant prostate tissues: cancer association of annexin A3.

A differential quantitative protein expression study, comparing matched prostate cancerous and benign tissues from 31 patients, revealed proteins newly associated with prostate cancer. Average effects for 17 proteins whose abundance was significantly different (p<0.01) across patients ranged from 1.5- to 6.1-fold, and included a number of known cancer markers. The most differentially abundant proteins between cancer and benign samples were isopeptidase T, serum amyloid P (SAP), annexin A3 (ANXA3) and mitochondrial enoyl coenzyme-A hydratase. SAP is restricted to stroma in healthy tissue, and the lower abundance in tumours may be explained by the reduced stromal content. ANXA3 is present in healthy epithelial cells, exhibits strong staining in precancerous prostatic intraepithelial neoplasia, and is relatively less abundant in individual tumour cells of increasing Gleason pattern (GP), despite exhibiting higher overall tissue abundance in tumours. ANXA3 staining was predominantly cytoplasmic, yet nuclear localization was also observed. Strongly staining single cells, possibly phagocytes, were interspersed in highly dedifferentiated GP5 tumour areas among tumour cells without measurable ANXA3. Local recurrent androgen ablation therapy-resistant tumours exhibit heterogenous low levels of ANXA3 staining. Results are discussed focussing on the potential implications for tumour tissues.

Adult↗

PubMed2005

Annexin A3 is a potential angiogenic mediator.

Angiogenesis is a complex process that is regulated by a variety of angiogenic activators and inhibitors. Disruption of the balanced angiogenesis leads to the progress of diseases such as tumor growth, rheumatoid arthritis, and various blood vessel-related disorders. Even though a number of proteins involved in angiogenesis have been identified so far, more protein factors remain to be identified due to complexity of the process. Here we report that annexin A3 (ANXA3) induces migration and tube formation of human umbilical vein endothelial cells. High level of vascular endothelial growth factor (VEGF), a prominent angiogenic factor, is also detected in conditioned medium obtained from cells transfected with ANXA3 expression plasmid. Reporter assays show that ANXA3 enhances hypoxia-inducible factor-1 (HIF-1) transactivation activity. Taken together, our results suggest that ANXA3 is a novel angiogenic factor that induces VEGF production through the HIF-1 pathway.

Annexin A3↗

PubMed2006

Change in annexin A3 expression by regulatory factors of hepatocyte growth in primary cultured rat hepatocytes.

We have recently reported that annexin (Anx) A3 expression is necessary for hepatocyte growth in cultured rat hepatocytes seeded at half the subconfluent density on collagen. In the present study, we investigated the effects of various regulatory factors of hepatocyte growth on AnxA3 expression. AnxA3 expression was significantly reduced in hepatocytes cultured under various growth inhibitory conditions such as presence of dexamethasone, culture at subconfluent cell density, and on EHS-Matrigel and lactose-carrying styrene polymer. On the other hand, hepatocyte growth factor and epidermal growth factor, stimulators of hepatocyte growth, significantly increased AnxA3 expression in hepatocytes cultured on EHS-Matrigel. These results show close correlation between known stimulatory or inhibitory actions of various factors to hepatocyte growth and increase or decrease in AnxA3 expression, and suggest the involvement of AnxA3 in their regulation of hepatocyte growth.

Animals↗

PubMed2000

The annexin A3-membrane interaction is modulated by an N-terminal tryptophan.

The crystal structure of annexin A3 (human annexin III) solved recently revealed a well-ordered folding of its N-terminus with the side chain of tryptophan 5 interacting with residues at the extremity of the central pore. Since the pore of annexins has been suggested as the ion pathway involved in membrane permeabilization by these proteins, we investigated the effect of the N-terminal tryptophan on the channel activity of annexin A3 by a comparative study of the wild-type and the W5A mutant in structural and functional aspects. Calcium influx and patch-clamp recordings revealed that the mutant exhibited an enhanced membrane permeabilization activity as compared to the wild-type protein. Analysis of the phospholipid binding behavior of wild-type and mutant protein was carried out by cosedimentation with lipids and inhibition of PLA(2) activity. Both methods reveal a much stronger binding of the mutant to phospholipids. The structure is very similar for the wild-type and the mutant protein. The exchange of the tryptophan for an alanine results in a disordered N-terminal segment. Urea-induced denaturation of the wild-type and mutant monitored by intrinsic fluorescence indicates a separate unfolding of the N-terminal region which occurs at lower urea concentrations than unfolding of the protein core. We therefore conclude that the N-terminal domain of annexin A3, and especially tryptophan 5, is involved in the modulation of membrane binding and permeabilization by annexin A3.

Alanine↗

PubMed2006

[Proteomic analysis of human ovarian cancer cell lines and their platinum-resistant clones].

OBJECTIVE: To perform comparative proteomic analysis of human ovarian cancer cell lines for detecting platinum-resistance associated proteins. METHODS: The total proteins of two sensitive (SKOV3 and A2780) and four resistant (SKOV3/CDDP, SKOV3/CBP, A2780/CDDP and A2780/CBP) human ovarian cancer cell lines were separated by two-dimensional gel electrophoresis (2-DE). The differentially expressed proteins were analyzed using image analysis software, stained with Coomassie Brilliant Blue, then identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and database searching. The mRNA and protein levels of the differentially expressed protein which was most significant in all of the four resistant cell lines were validated by RT-PCR and western blotting, respectively. RESULTS: Five proteins were found to be significant in four cell lines. Annexin A3 and destrin were up-regulated and nicotinamide-adenine dinucleotide phosphate (NADP)-dependent isocitrate dehydrogenase 1 was down-regulated in all the four resistant samples. Glutathione transferase omega 1 had an increased expression in the other three resistant cell lines except for SKOV3/CBP in which its expression was not changed. However, cofilin 1 represented a different trend. In the two resistant sublines of SKOV3, cofilin 1 had a down-regulation, but it had an up-regulation in the cell lines induced from SKOV3. The expression of annexin A3 was up-regulated by 3 - 20 fold and the results of RT-PCR and western blotting showed complete consistency with that by 2-DE. CONCLUSIONS: Proteomic techniques are useful to the identification of the resistance-associated proteins in ovarian cancer platinum-resistant cell lines and five candidates have been found. The five differential proteins might become hopeful candidate biomarkers for resistance.

Annexin A3↗

PubMed2025

ANXA3 hypomethylation as a prognostic biomarker in hepatitis B virus-related acute-on-chronic liver failure.

BACKGROUND: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is associated with a poor prognosis. This research aimed to characterize the expression pattern and clinical value of Annexin A3 (ANXA3) in HBV-ACLF patients. METHODS: First of all, ACLF-related datasets were downloaded from the Gene Expression Omnibus (GEO) database to carry out bioinformatics analyses. RT-qPCR, ELISA, and Methylight were used to measure ANXA3 gene expression and promoter methylation levels. A validation cohort was leveraged to further validate the results. RESULTS: Transcriptome analysis showed that ANXA3 was among the most differentially expressed genes when comparing dead patients with HBV-ACLF to those with survivors. The mRNA and serum levels of ANXA3 were elevated, and methylation levels were decreased in HBV-ACLF patients. The PMR value of ANXA3 in patients with HBV-ACLF was negatively correlated with inflammation-related cytokines IL-6, TNF-α, and IL-1β, as well as quantitative clinical parameters AST, TBIL, PT, INR, NEUT%, and MELD score, and positively correlated with PTA (all p < 0.05). In HBV-ACLF patients, ANXA3 was considered to be an independent influence factor for the 90-day mortality. It was also found that ANXA3, especially hypomethylation, was associated with 28- and 90-day overall survival in patients with HBV-ACLF based on receiver operating characteristic (ROC) analysis, decision curve analysis (DCA), and Kaplan-Meier curves. CONCLUSIONS: ANXA3 hypomethylation has a prominent predictive value for short-term mortality in patients with HBV-ACLF and may serve as a promising biomarker of HBV-ACLF prognosis.

Humans↗

PubMed2005

Alterations in mouse cardiac proteome after in vivo myocardial infarction: permanent ischaemia versus ischaemia-reperfusion.

Mice are increasingly used to study the early molecular mechanisms inducing injury to the heart following myocardial infarction. To date, two-dimensional gel electrophoresis combined with mass spectrometry has not been applied to identify changes in protein expression in myocardial tissue of mice subjected in vivo to permanent ischaemia (PI) or ischaemia-reperfusion (IR). In the PI group, ischaemia was induced for 210 min by ligation of the left anterior descending coronary artery while in the IR group, ischaemia was maintained for 30 min and reperfusion was allowed for 180 min. In both groups, the area of the left ventricle at risk was processed for 2-dimensional gel electrophoresis. By comparing protein density changes in cytosolic as well as membrane fractions, we found a total of 32 protein spots that were differentially expressed. Twenty spots changed in expression level after PI alone, four spots after IR alone, and eight spots changed in both models. Identified proteins with MALDI TOF-TOF and LC-MS/MS can be classified into functional groups of anticoagulant proteins, structural proteins, inflammatory-related proteins, transcription- and translation-related proteins, heat shock proteins (HSPs), metabolism-related proteins and miscellaneous. A remarkable finding was the IR-specific translocation of annexins (A3 and A5) from the cytosolic to the membrane compartment, a phenomenon that was verified by Western blotting. Four proteins were changed in expression level at multiple spot locations, characterized by a difference in isoelectric point. In the case of cardiac troponin T and HSP-20, these changes were also dependent on the model. In addition, one spot for the proteins adenylate kinase 1, cardiac troponin T and HSP-20 was uniquely present in the IR and/or PI groups and not in the respective sham groups. The specific alterations in protein expression that took place after PI and IR may stimulate the search for new tools to diagnoze myocardial infarction and to characterize specific pathology-related changes in protein expression.

Animals↗

PubMed1996

Differential expression of annexins I-VI in the rat dorsal root ganglia and spinal cord.

The annexins are a family of Ca(2+)-dependent phospholipid-binding proteins. In the present study, the spatial expression patterns of annexins I-VI were evaluated in the rat dorsal root ganglia (DRG) and spinal cord (SC) by using indirect immunofluorescence. Annexin I is expressed in small sensory neurons of the DRG, by most neurons of the SC, and by ependymal cells lining the central canal. Annexin II is expressed by most sensory neurons of the DRG but is primarily expressed in the SC by glial cells. Annexin III is expressed by most sensory neurons, regardless of size, by endothelial cells lining the blood vessels, and by the perineurium. In the SC, annexin III is primarily expressed by astrocytes. In the DRG and the SC, annexin IV is primarily expressed by glial cells and at lower levels by neurons. In the DRG, annexin V is expressed in relatively high concentrations in small sensory neurons in contrast to the SC, where it is expressed mainly by ependymal cells and by small-diameter axons located in the superficial laminae of the dorsal horn areas. Annexin VI is differentially expressed by sensory neurons of the DRG, being more concentrated in small neurons. In the SC, annexin VI has the most striking distribution. It is concentrated subjacent to the plasma membrane of motor neurons and their processes. The differential localization pattern of annexins in cells of the SC and DRG could reflect their individual biological roles in Ca(2+)-signal transduction within the central nervous system.

Animals↗

PubMed1997

Structural analysis of junctions formed between lipid membranes and several annexins by cryo-electron microscopy.

The (annexin II-p11)2 tetramer has been proposed to participate in exocytosis and several other members of the annexin superfamily have been reported to aggregate liposomes in vitro. In this context, the Ca2+-dependent binding of several annexins to chromaffin granules and liposomes was investigated by cryo-electron microscopy. The Ca2+-dependent aggregation of lipid membranes by (annexin II-p11)2 results from the spontaneous self-organization of the protein into two-dimensional plaques, which are visualized in projection as characteristic junctions. The junctions have a constant thickness of 210(+/-10) A and present a symmetrical distribution of electron-dense material arranged into seven stripes. They were observed over a wide range of Ca2+ concentrations, down to 2 microM. The molecular components corresponding to the seven electron-dense stripes were assigned as follows: the two associated membranes give rise to two outer stripes each and the three central stripes correspond to the (annexin II-p11)2 tetramer. Each annexin II molecule interacts with the outer lipid leaflet of one membrane, giving rise to one stripe, while the central stripe is due to the (p11)2 dimer with which both annexin II molecules interact. Both annexin II and annexin I also induced the Ca2+-dependent aggregation of liposomes via junctions that lack the central (p11)2 moiety and present only six high-density stripes. As expected, both annexin V and annexin III bind to liposomes without inducing their aggregation.

Animals↗

PubMed2001

Calcium-dependent association of annexins with lipid bilayers modifies gramicidin A channel parameters.

In order to examine whether calcium-dependent binding of annexin to acidic phospholipids could change the lipid bilayer environment sufficiently to perturb channel-mediated transmembrane ion-transport, gramicidin A channel activity in planar lipid bilayers was investigated in the presence of calcium and annexins II, III or V. The experiments were performed with membranes consisting of phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine in 300 mM KCl solution buffered to pH 7.4 and with either 0.1 or 1 mM calcium added to the solution. Annexin (1 microM) was subsequently applied to the cis side of the membrane. All three annexins (II, III and V) when tested at 1 mM calcium decreased the gramicidin single-channel conductance. Annexins II and III increased the mean lifetime of the channels whereas annexin V seemed to have no influence on the mean lifetime. Since the lifetime of gramicidin A channels is a function of the rate constant for dissociation of the gramicidin dimer, which is dependent on the physical properties of the lipid phase, binding of annexins II and III seems to stabilize the gramicidin channel owing to a change of the bilayer structure.

Animals↗

PubMed1997

Annexins from Ehrlich ascites cells inhibit the calcium-activated chloride current in Xenopus laevis oocytes.

The effect of annexins II, III and V, purified from different species, on the calcium-activated chloride current across the stage-V to stage-VI Xenopus laevis oocyte membrane was tested either directly, using calcium entry mediated by depolarization, by A23187 permeabilization of oocytes or indirectly by quisqualate stimulation of a metabotropic glutamate receptor in the membrane expressed by the oocyte after injection of mRNA. The annexins isolated from the Ehrlich ascites cell, which is a mouse tumor cell, were found to be potent inhibitors of the chloride current, showing half-maximal inhibition at 50 nM, whereas no block was found using bovine or porcine annexins isolated from lung tissue. Of the annexins tested, we found annexin III to be naturally occurring in the oocyte, while only trace amounts of annexins II and V could be demonstrated. The inhibition pattern varied somewhat according to the stimulus method, the inhibition being more complete when an indirect stimulus via the metabotropic receptor was applied compared to a direct calcium stimulus.

Animals↗

PubMed2001

Differential effects of annexins I, II, III, and V on cytosolic phospholipase A2 activity: specific interaction model.

Annexins (ANXs) are a family of proteins with calcium-dependent phospholipid binding properties. Although inhibition of phospholipase A2 (PLA2) by ANX-I has been reported, the mechanism is still controversial. Previously we proposed a 'specific interaction' model for the mechanism of cytosolic PLA2 (cPLA2) inhibition by ANX-I [Kim et al., FEBS Lett. 343 (1994) 251-255]. Here we have studied the cPLA2 inhibition mechanism using ANX-I, N-terminally deleted ANX-I (DeltaANX-I), ANX-II, ANX-II(2)P11(2), ANX-III, and ANX-V. Under the conditions for the specific interaction model, ANX-I, DeltaANX-I, and ANX-II(2)P11(2) inhibited cPLA2, whereas inhibition by ANX-II and ANX-III was negligible. Inhibition by ANX-V was much smaller than that by ANX-I. The protein-protein interactions between cPLA2 and ANX-I, DeltaANX-I, and ANX-II(2)P11(2) were verified by immunoprecipitation. We can therefore conclude that inhibition of cPLA2 by specific interaction is not a general function of all ANXs, and is rather a specific function of ANX-I. The results are consistent with the specific interaction model.

Animals↗

PubMed1996

The high-resolution crystal structure of human annexin III shows subtle differences with annexin V.

The structure of recombinant human annexin III was solved to 1.8 A resolution. Though homologous to annexin I and V, the annexin III structure shows significant differences. The tryptophan in the calcium loop of the third domain is exposed to the solvent, as in the structure of annexin V crystallized in high calcium concentrations, although the annexin III crystals were prepared at low calcium concentrations. The position of domain III relative to the other domains is different from both annexin V and I, suggesting further flexibility of the molecule. The entire N-terminus of the protein is well-defined in the present structure. The side chain of tryptophan 5 interacts with the hinge region of the hydrophillic channel, which could have an effect on the potential mobility of this region, as well as on its possible calcium channel behavior.

Annexin A1↗

PubMed1998

Interactions of benzodiazepine derivatives with annexins.

Human annexins III and V, members of the annexin family of calcium- and membrane-binding proteins, were complexed within the crystals with BDA452, a new 1,4-benzodiazepine derivative by soaking and co-crystallization methods. The crystal structures of the complexes were analyzed by x-ray crystallography and refined to 2.3- and 3.0-A resolution. BDA452 binds to a cleft which is located close to the N-terminus opposite to the membrane binding side of the proteins. Biophysical studies of the interactions of various benzodiazepine derivatives with annexins were performed to analyze the binding of benzodiazepines to annexins and their effects on the annexin-induced calcium influx into phosphatidylserine/phosphatidylethanolamine liposomes. Different effects were observed with a variety of benzodiazepines and different annexins depending on both the ligand and the protein. Almost opposite effects on annexin function are elicited by BDA250 and diazepam, its 7-chloro-derivative. We conclude that benzodiazepines modulate the calcium influx activity of annexins allosterically by stabilizing or destabilizing the conducting state of peripherally bound annexins in agreement with suggestions by Kaneko (Kaneko, N., Ago, H., Matsuda, R., Inagaki, E., and Miyano, M. (1997) J. Mol. Biol., in press).

Amino Acid Sequence↗

PubMed1993

Structure-function correlations of calcium binding and calcium channel activities based on 3-dimensional models of human annexins I, II, III, V and VII.

The annexins are a family of calcium-dependent phospholipid-binding proteins which share a high degree of primary sequence similarity. Using a model of the crystal structure of annexin V as a template, 3-dimensional models of human annexins I, II, III and VII were constructed by homology modeling (J. Greer, J. Mol. Biol. 153, 1027-1042, 1981; J.M. Chen, G. Lee, R.B. Murphy, R.P. Carty, P.W. Brant-Rauf, E. Friedman and M.R. Pincus, J. Biomolec. Str. Dyn. 6, 859-87, 1989) for the 316 amino acid portions corresponding to the annexin V structure published by Huber et al. (J. Mol. Biol. 223, 683-704, 1992). These methods were used to study structure-function correlations for calcium ion binding and calcium channel activity. Published experimental data are specifically shown to be consistent with the annexin models. Possible intramolecular disulfide bridges were identified in annexin I (between Cys297 and Cys316) and in annexins II and VII (between Cys115 and Cys243). Each of the annexin models have 3 postulated calcium binding sites, usually via a Gly-Xxx-Gly-Thr loop with an acidic Glu or Asp residue 42 positions C-terminal to the first Gly. Despite a nonconserved binding site sequence, annexins I and II are able to coordinate calcium in domain 3 since the residue in the second loop position is directed toward the solvent away from the binding pocket. This finding also suggests a mechanism for a conformational change upon binding calcium. Highly conserved Arg and acidic sidechains stabilize the channel pore structure; annexin channels probably exist in a closed state normally. Arg271 may be involved in channel opening upon activation: basic residue 254 can stabilize Glu112, which allows Arg271 to interact with residue 95 instead of Glu112. Residue 267, found on the convex surface at the pore opening, may also be important in modifying channel activity.

Amino Acid Sequence↗

PubMed1994

Homology modelling of annexin I: implicit solvation improves side-chain prediction and combination of evaluation criteria allows recognition of different types of conformational error.

Annexin I homology models were built from the annexin V crystal structure. Three methods for side-chain prediction were tested based on molecular mechanics conformational search, the use of a rotamer database, or a combination of these two methods. We showed that rotamer-based methods were more efficient and that molecular mechanics energy minimizations, prior to rotamer selection, did not afford clearly improved predictions. Models built in vacuo and with an implicit solvation term were compared with the annexin I crystal structure which became available during the course of this study. The analysis of solvation energies, root mean square deviations, chi 1 angles and hydrogen bonds showed that models built with implicit solvation were of better quality. In annexin V, repeat III displays A-B and D-E loop conformations quite different from other repeats. Since the sequence differences suggest that repeat III in annexin I might present a conformation similar to other repeats, two annexin I models with different repeat III conformations were built and compared to determine whether the correct conformation could have been predicted. We show that using a combination of evaluation criteria, it is possible to discriminate unequivocally between the native and the incorrect fold, stressing that only one criterion should not be used to evaluate protein structures.

Amino Acid Sequence↗