Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08758 (annexin V)
 9,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 32 kDa protein isolated from human mononuclear cells is a member of the lipocortin family, a new group of Ca2+-dependent lipid-binding proteins thought to be involved in the regulation of phospholipase A2, in exocytosis and in membrane-cytoskeleton interactions. Purification of this protein was based on its ability to associate with membrane phospholipids in a Ca2+-dependent manner and its capacity to inhibit purified phospholipase A2 from pig pancreas. Using immunological detection, we show that it is present in various cells involved in the inflammatory and coagulation processes. We present extensive amino acid data that strongly suggest that this protein is identical with a recently described inhibitor of blood coagulation, with endonexin II and with lipocortin V. Sequence alignment with other known proteins show a significant degree of homology with lipocortins I and II, the substrates of the epidermal-growth-factor receptor tyrosine kinase and the oncogene pp60src tyrosine kinase respectively, and with protein II. The possible physiological role of this 32 kDa lipocortin is discussed.
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PMID:A 32 kDa lipocortin from human mononuclear cells appears to be identical with the placental inhibitor of blood coagulation. 253 7

Previously we isolated and characterized a placental anticoagulant protein (PAP or PAP-I), which is a Ca2+-dependent phospholipid binding protein [Funakoshi et al. (1987) Biochemistry 26, 5572] and a member of the lipocortin family [Funakoshi et al. (1987) Biochemistry 26, 8087]. In this study, three additional anticoagulant proteins (PAP-II, PAP-III, and PAP-IV) were simultaneously isolated from human placental homogenates prepared in the presence of 5 mM ethylenediaminetetraacetic acid. The isoelectric points of PAP-I, PAP-II, PAP-III, and PAP-IV were 4.8, 6.1, 5.9, and 8.1, respectively, and their apparent molecular weights were 32,000, 33,000, 34,000, and 34,500, respectively. Amino acid sequences of cyanogen bromide fragments of these proteins showed that PAP-III was a previously unrecognized member of the lipocortin family, while PAP-II was probably the human homologue of porcine protein II and PAP-IV was a derivative of lipocortin II truncated near the amino terminus. Comparative studies showed that all four proteins inhibited blood clotting and phospholipase A2 activity with potencies consistent with their measured relative affinities for anionic phospholipid vesicles. However, PAP-IV bound to phospholipid vesicles approximately 160-fold more weakly than PAP-I, while PAP-II and PAP-III bound only 2-fold and 3-fold more weakly. These results increase to six the number of lipocortin-like proteins known to exist in human placenta. The observed differences in phospholipid binding may indicate functional differences among the members of the lipocortin family despite their considerable structural similarities.
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PMID:Placental anticoagulant proteins: isolation and comparative characterization four members of the lipocortin family. 297 6

Porcine thyroid cells cultured in the presence of TSH (0.1 mU/ml) or forskolin (10(-5) M) for 4 days display an increased annexin I, II, V biosynthesis when compared with unstimulated cells. Annexin I mostly accumulates in the cytosolic fraction and annexins II and V in the particulate fraction. TSH and forskolin affect in the same manner annexin biosynthesis and localization. In the TSH and forskolin treated cells PGE2 production is very low in comparison with the very high PLA2 activity observed in the dedifferentiated control cells. A strong inhibition of the PGE2 production is observed in control cells incubated with a purified annexin V preparation. These results suggest the existence, in porcine thyroid cells, of a cross-talk between the adenylyl cyclase system and the phospholipase A2 mediated pathways. Annexins' biosynthesis and localization are under the control of the adenylyl cyclase system and participate in this cross-talk.
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PMID:Cyclic AMP regulation of annexins I, II, V synthesis and localization in cultured porcine thyroid cells. 784 8

Annexin V is a phospholipase A2 and protein kinase C inhibitory protein with calcium channel activity and an undefined role in cellular signal transduction, inflammation, growth and differentiation. Three genomic clones for human annexin V (ANX5) were characterized by restriction analysis, Southern blotting and sequencing. ANX5 spans at least 29 kb of the human genome and contains 13 exons ranging in length from 44 to 513 bp and 12 introns from 232 bp to 8 kb. The absence of a typical TATA box and the presence of high G+C content and Sp1-binding sites in its promoter characterize it as a 'housekeeping' gene and account for its broad pattern of expression. Potential binding sites for cis-regulatory elements identified in the 5'-upstream region of annexin V are consistent with its known regulation by oncogenic and growth-related stimuli. ANX5, like its chick homologue, differs from the genes encoding annexins I, II and III in features of its promoter and in the size of its exons 1, 2 and 3 in ways that may impart individuality to its regulation and function.
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PMID:The gene encoding human annexin V has a TATA-less promoter with a high G+C content. 795 98

We have studied the expression of the cellular, type two phospholipase A2 and lipocortins (annexins) I, II and V in human amnion, chorion-decidua and placenta using northern analysis. We found no difference in the expression of phospholipase A2 or lipocortin V in tissues obtained before or after labour. Lipocortin I expression was found to decrease in amnion and placenta but increase in chorion decidua with the onset of labour, while expression of lipocortin II increased only in amnion. These results support the hypothesis that the increased phospholipase A2 activity in the fetal membranes and placenta which is associated with labour is not due to increased phospholipase A2 gene expression, but that post translational control of phospholipase A2 activity may be mediated through changes in lipocortin I expression.
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PMID:The expression of phospholipase A2 and lipocortins (annexins) I, II and V in human fetal membranes and placenta in association with labour. 799 77

Annexin V is part of a family of Ca(2+)-dependent phospholipid-binding proteins, whose purported functions are related to their interactions with biological membranes. While Ca(2+)-dependent binding to phospholipids is well-established, the specific structural interactions within the phospholipid-binding sites have only been inferred to resemble those of phospholipase A2, with no direct structural evidence. In this study, the binding avidity of various phospholipid analogs, with variations at the headgroup or sn-2 acyl chain, was monitored in a C12E8 detergent micelle system using the increase in fluorescence of tryptophan 187. Micelles also contained excess negative surface charge to saturate a nonspecific component of the binding. The Ca2+ and phospholipid concentrations required for the binding of annexin V to various phospholipid headgroups were very similar, except for the relatively weak binding to phosphatidylinositol (PI). The unique close proximity of the PI sugar ring to the phosphate group may lead to steric hindrance in this case. Binding was also strongly dependent on the presence of an sn-3 phosphate group and an sn-2 acyl chain, as previously observed. The relatively shallow nature of the annexin V phospholipid-binding sites was reflected by the nearly equivalent binding of D and L versions of phospholipids, i.e., a large shift in the position of the sn-1 acyl chain is accommodated in this case. Binding of annexin V does not specifically require an ester carbonyl oxygen, as it occurs with ether-linked, amide-linked, and phosphonate-linked sn-2 hydrocarbon chains, under these conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phospholipid determinants for annexin V binding sites and the role of tryptophan 187. 818 Feb 11

Annexin V belongs to a family of proteins that interact with phospholipids in a Ca2+-dependent manner. This protein has been demonstrated to have anti-phospholipase A2 activity. However, this effect has never yet been reported with the 85-kDa cytosolic PLA2 (cPLA2). We studied, in a model of differentiated and streptolysin O-permeabilized HL-60 cells, the effect of annexin V on cPLA2 activity after stimulation by calcium, GTPgammaS (guanosine 5'-O-(3-thiotriphosphate)), formyl-Met-Leu-Phe, or phorbol 12-myristate 13-acetate. Both recombinant and human placental purified annexin V inhibit cPLA2 activity whatever the stimulus used. The decrease of arachidonic acid release is of 40 and 50%, respectively, at [Ca2+] of 3 and 10 microM. The mechanism of inhibition was also analyzed. cPLA2 requires calcium and protein kinase C (PKC) or mitogen-activated protein kinase phosphorylation for its activation. As annexin V was shown to be an endogenous inhibitor of PKC, PKC-stimulated cPLA2 activity was analyzed. Using GF109203x, a specific PKC inhibitor, we demonstrated that this pathway is of minor importance in our model. cPLA2 inhibition by annexin V is not linked to PKC inhibition. To test the hypothesis of phospholipid depletion, mutants of annexin V were constructed using mutagenesis directed to Ca2+ site. We demonstrate that the Ca2+ site located in domain I is necessary for the inhibitory effect of annexin V on cPLA2 activity. The site in domain IV is also involved but with less efficiency. In contrast, mutations in site II and III do not modify this effect. Moreover, annexin V mutated on all sites does not inhibit cPLA2. Thus, we propose a predominant role of module (I/IV) in the biological action of annexin V, which, in physiological conditions, may control cPLA2 activity by depletion of the phospholipid substrate.
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PMID:Inhibition of cytosolic phospholipase A2 by annexin V in differentiated permeabilized HL-60 cells. Evidence of crucial importance of domain I type II Ca2+-binding site in the mechanism of inhibition. 909 90

This study explored whether annexin V, a protein with established phospholipase A2 inhibiting properties, plays a role in the degradation of membrane phospholipids of adult cardiac myocytes during metabolic inhibition (20 mM 2-deoxyglucose and 1 mM iodoacetic acid). Experiments were carried out on isolated cardiac myocytes prelabeled with [14C]-arachidonic acid, which were subjected to metabolic inhibition for up to 240 min. Under control conditions, annexin V was found to be localised predominantly at the sarcolemma. After 120 min of metabolic inhibition, the release of lactate dehydrogenase (LDH) was still comparable with control cells, while morphological changes were already visible. After 240 min of metabolic inhibition, LDH release was significantly elevated compared to control cells incubated for the same period of time (35% v 20% of total cellular activity). All myocytes had lost their typical elongated shape and sarcolemmal "blebs" had been formed. In metabolically inhibited cells, annexin V localisation seemed to be more pronounced at the level of the sarcolemma compared to controls, whereas membrane phospholipid hydrolysis occurred at a significantly elevated rate, as evidenced by a significantly enhanced accumulation of labeled arachidonic acid within the cells. The present findings are not in favor of the hypothesis that the increase in net degradation of phospholipids in energy-deprived cardiac myocytes is caused by a loss of annexin V from the sarcolemma, which would increase the vulnerability of the sarcolemma to phospholipase A2 activity.
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PMID:Phospholipid degradation in energy-deprived cardiac myocytes: does annexin V play a role? 920 25

The ability of annexins, particularly annexin 1 (lipocortin 1), to inhibit phospholipase A2 (PLA2) is well known and a substrate depletion mechanism is now widely accepted as the explanation for most inhibitory studies. However, there are only a very limited number of reported studies involving annexins and the high-molecular-mass cytosolic PLA2 (cPLA2). In this study we have examined the effect of human recombinant annexin V, a potentially abundant cytosolic protein, on the ability of human recombinant cPLA2 to hydrolyse a variety of phospholipid substrates. The results show clearly that, under the conditions of our study, annexin V can inhibit cPLA2 activity by a mechanism of substrate depletion and that this inhibition is dependent on the nature of the phospholipids and the concentration of Ca2+ ions in the assay. The hydrolysis of 1-stearoyl 2-arachidonyl phosphatidylcholine by cPLA2 was not significantly affected by annexin V over a range of Ca2+ concentrations (1 microM-2.5 mM), a result that presumably reflects the zwitterionic nature of the phospholipid and the known inability of annexins to bind to such interfaces. In contrast, the hydrolysis of dioleoyl phosphatidylglycerol, which is an effective anionic phospholipid substrate for this enzyme, and more significantly that of 1-stearoyl 2-arachidonyl phosphatidic acid, were readily inhibited by annexin V, although these effects were Ca2+-dependent. The Ca2+ concentrations required for inhibition in the assay system in vitro are greater than those associated with Ca2+-stimulated events within the cell, suggesting that a role for annexin V in regulating cPLA2 activity might not involve a substrate depletion mechanism in vivo unless factors in addition to Ca2+ and phospholipids contribute to the binding of annexin V to cell membranes.
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PMID:Inhibition of human cytosolic phospholipase A2 by human annexin V. 942 21

The ability of annexins, particularly annexin 1 (lipocortin 1), to inhibit phospholipase A2 (PLA2) is well known and a substrate depletion mechanism is now widely accepted as the explanation for most inhibitory studies. In this investigation we have examined the substrate depletion mechanism of annexin V using a variety of phospholipid substrates and secreted PLA2's (sPLA2). The results suggest that the term interfacial competition best describes the inhibitory effect of annexin V although the overall inhibitory process remains one of substrate sequestration by the annexin. We have utilised the competitive nature of the interaction of enzyme and annexin V for a phospholipid interface as a means of quantifying the relative affinity of sPLA2's for anionic phospholipid vesicles. The results highlight the very high affinity of the human non-pancreatic sPLA2 for such vesicles (Kd<<10-(10) M) while the Naja naja venom PLA2 and porcine pancreatic sPLA2 showed lower affinities. Hydrolysis of mixed vesicles containing phosphatidylserine and phosphatidylcholine by the venom and pancreatic enzymes were differentially inhibited by annexin V. This difference must reflect the preference of both annexin V and the pancreatic enzyme for an anionic phospholipid interface. In contrast, the venom enzyme is able to readily hydrolyse phosphatidylcholine domains that would be minimally affected by annexin V. Annexin V was an effective inhibitor of cardiolipin hydrolysis by the pancreatic PLA2, however the inhibition was of a more complex nature than seen with other phospholipids tested. Overall the results highlight the ability of annexin V to inhibit phospholipid hydrolysis by sPLA2's by an interfacial competition (substrate depletion) mechanism. The effectiveness of annexin V as an apparent inhibitor depends on the nature of the enzyme and the phospholipid substrate.
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PMID:Inhibition of secreted phospholipases A2 by annexin V. Competition for anionic phospholipid interfaces allows an assessment of the relative interfacial affinities of secreted phospholipases A2. 955 96


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