Cholesterol Enhances Phospholipid Binding and Aggregation of Annexins by Their Core Domain

Ayala-Sanmartín, Jesús

doi:10.1006/bbrc.2001.4748

Cited by 62 publications

(67 citation statements)

References 58 publications

(67 reference statements)

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“…It has been reported that cholesterol increases the affinity of annexin A2 for anionic vesicles (63) and regulates the subcellular distribution of annexin A2 (24). Our SPR measurements show, however, that annexin A2 does not bind cholesterol itself, which is consistent with a recent report on the binding of A2t to solid-supported lipid membranes (64).…”

Section: Discussionsupporting

confidence: 92%

Phosphoinositide Specificity of and Mechanism of Lipid Domain Formation by Annexin A2-p11 Heterotetramer

Gokhale

Abraham

Digman

et al. 2005

Journal of Biological Chemistry

104

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Annexin A2 is a phospholipid-binding protein that forms a heterotetramer (annexin II-p11 heterotetramer; A2t) with p11 (S100A10). It has been reported that annexin A2 is involved in binding to phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P 2 ) and in inducing membrane microdomain formation. To understand the mechanisms underlying these findings, we determined the membrane binding properties of annexin A2 wild type and mutants both as monomer and as A2t. Our results from surface plasmon resonance analysis showed that A2t and annexin A2 has modest selectivity for PtdIns(4,5)P 2 over other phosphoinositides, which is conferred by conserved basic residues, including Lys 279 and Lys 281 , on the convex surface of annexin A2. Fluorescence microscopy measurements using giant unilamellar vesicles showed that A2t of wild type, but not (K279A) 2 -(p11) 2 or (K281A) 2 -(p11) 2 , specifically induced the formation of 1-m-sized PtdIns(4,5)P 2 clusters, which were stabilized by cholesterol. Collectively, these studies elucidate the structural determinant of the PtdIns(4,5)P 2 selectivity of A2t and suggest that A2t may be involved in the regulation of PtdIns(4,5)P 2 clustering in the cell.Annexins are a family of peripheral proteins that bind anionic phospholipids in a Ca 2ϩ -dependent manner (1-5). Structures and in vitro functions of annexins have been well characterized. Annexins have a variable N-terminal region and a conserved C-terminal core that is composed of four (eight in case of annexin A6) ␣-helical annexin folds (2). The C-terminal core is the Ca 2ϩ -dependent membrane-binding module that contains multiple Ca 2ϩ -binding sites on its convex membrane-binding surface (2). The N-terminal region of annexins is attached to the concave side of the C-terminal core and thought to be involved in interactions with other proteins and post-translational modifications (3-5). In addition to their membrane-binding activities, annexins have been reported to have other in vitro activities, including membrane aggregation and lateral aggregation on the membrane surface (6). Despite the wealth of structural and functional information on annexins, their physiological functions are only beginning to emerge with recent genetic and cell studies (3-5).Annexin A2 is an abundant cellular protein that has been implicated in numerous physiological processes (3-5, 7). Annexin A2 interacts with an EF-hand protein p11 (also known as S100A11) with high affinity via its N-terminal region, forming a symmetric heterotetramer, (annexin A2) 2 -(p11) 2 (A2t) 2 (8, 9). Annexin A2 has been reported to exist either as a monomer or A2t in mammalian cells (3, 10 -12). Annexin A2 and A2t have been shown to have high vesicle aggregating activity (13) and form a monolayer of protein clusters when bound to the lipid bilayer with anionic phospholipids accumulating underneath the protein clusters (14). Mounting evidence indicates that annexin A2 and A2t are involved in organizing cholesterol-rich lipid rafts (15, 16) and linking them to cytoskeletal protein...

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Section: Discussionsupporting

confidence: 92%

Phosphoinositide Specificity of and Mechanism of Lipid Domain Formation by Annexin A2-p11 Heterotetramer

Gokhale

Abraham

Digman

et al. 2005

Journal of Biological Chemistry

104

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“…Hence, all these data are compatible with a requirement of Ca 2+ for the translocation of annexin A5 to the lysosomal membranes. Moreover, annexin A5 shows a cholesterol-mediated enhancement of its Ca 2+ -dependent binding to membranes (Ayala-Sanmartin, 2001), and the importance of membrane cholesterol levels in the fusion of lysosomes with autophagosomes has also been reported (Massey et al, 2008). Thus, annexin A5 could induce autophagosome-lysosome fusion through cholesterol-rich domains in their membranes in a pH-and Ca 2+ -dependent way.…”

Section: Discussionmentioning

confidence: 88%

Annexin A5 stimulates autophagy and inhibits endocytosis

Ghislat

Aguado

Knecht

2012

Journal of Cell Science

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SummaryMacroautophagy is a major lysosomal catabolic process activated particularly under starvation in eukaryotic cells. A new organelle, the autophagosome, engulfs cytoplasmic substrates, which are degraded after fusion with endosomes and/or lysosomes. During a shotgun proteome analysis of purified lysosomal membranes from mouse fibroblasts, a Ca 2+ -dependent phospholipid-binding protein, annexin A5, was found to increase on lysosomal membranes under starvation. This suggests a role for this protein, an abundant annexin with a still unknown intracellular function, in starvation-induced lysosomal degradation. Transient overexpression and silencing experiments showed that annexin A5 increased lysosomal protein degradation, and colocalisation experiments, based on GFP sensitivity to lysosomal acidic pH, indicated that this was mainly the result of inducing autophagosome-lysosome fusion. Annexin A5 also inhibited the endocytosis of a fluid-phase marker and cholera toxin, but not receptor-mediated endocytosis. Therefore, we propose a double and opposite role of annexin A5 in regulating the endocytic and autophagic pathways and the fusion of autophagosomes with lysosomes and endosomes.

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“…Addition of cholesterol to liposome enhances the ability of AIIt to bind with and aggregate phosphatidylserine vesicles at submicromolar Ca 2ϩ levels. Cholesterol also alters the subcellular localization of AIIt at low Ca 2ϩ concentrations (25,26). Arachidonic acid enhances AIIt-mediated fusion in model membranes (13).…”

mentioning

confidence: 99%

“…Other groups also used liposomes to mimic granule membrane or plasma membrane (10,15,16,21,22,25). However, a direct biochemical analysis of the ability of AIIt to fuse plasma membrane with lamellar bodies or other granule membranes has not been reported.…”

mentioning

confidence: 99%

Fusion of Lamellar Body with Plasma Membrane Is Driven by the Dual Action of Annexin II Tetramer and Arachidonic Acid

Chattopadhyay

Sun

Wang

et al. 2003

Journal of Biological Chemistry

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Annexin II has been implicated in membrane fusion during the exocytosis of lamellar bodies from alveolar epithelial type II cells. Most previous studies were based on the fusion assays by using model membranes. In the present study, we investigated annexin II-mediated membrane fusion by using isolated lamellar bodies and plasma membrane as determined by the relief of octadecyl rhodamine B (R18) self-quenching. Immunodepletion of annexin II from type II cell cytosol reduced its fusion activity. Purified annexin II tetramer (AIIt) induced the fusion of lamellar bodies with the plasma membrane in a dose-dependent manner. This fusion is Ca 2؉ -dependent and is highly specific to AIIt because other annexins (I and II monomer, III, IV, V, and VI) were unable to induce the fusion. Modification of the different functional residues of AIIt by N-ethylmaleimide, nitric oxide, or peroxynitrite abolished AIIt-mediated fusion. Arachidonic acid enhanced AIIt-mediated fusion and reduced its Ca 2؉ requirement to an intracellularly achievable level. This effect is due to membranebound arachidonic acid, not free arachidonic acid. Other fatty acids including linolenic acid, palmitoleic acid, myristoleic acid, stearic acid, palmitic acid, and myristic acid had little effect. AIIt-mediated fusion was suppressed by the removal of arachidonic acid from lamellar body and plasma membrane using bovine serum albumin. The addition of arachidonic acid back to the arachidonic acid-depleted membranes restored its fusion activity. Our results suggest that the fusion between lamellar bodies with the plasma membrane is driven by the synergistic action of AIIt and arachidonic acid.Lung surfactant is a surface active material synthesized and secreted by cuboidal alveolar type II cells (1-3). It is composed of phospholipids, mainly dipalmitoylphosphatidylcholine, and surfactant proteins A-D. It minimizes the surface tension at the air-liquid interface by inserting phospholipids between water molecules. As a result, surfactant disrupts the cohesive hydrogen bonds and prevents them from exerting high molecular forces at the alveolar surface. Deficiency of dipalmitoylphosphatidylcholine in the alveolar surface has been associated with infant respiratory distress syndrome.The secretion of surfactant by type II cells involves the translocation, docking, and fusion of lamellar bodies to the plasma membrane. For the lamellar body content to reach its extracellular destination, a continuity of the vesicular lumen and extracellular fluid must be established. This continuity is maintained through the formation of a narrow pore similar to membrane channels (4 -6). The formation of this pore is a complex event involving physical and chemical factors and is regulated by intracellular Ca 2ϩ and proteins (7). Studies on mast cells and chromaffin cells revealed that the opening of fusion pore and extrusion of granule content is influenced by an osmotic force depending upon the osmolarity of the surrounding solution (8).Annexin II plays multidimensional roles in dif...

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Cholesterol Enhances Phospholipid Binding and Aggregation of Annexins by Their Core Domain

Cited by 62 publications

References 58 publications

Phosphoinositide Specificity of and Mechanism of Lipid Domain Formation by Annexin A2-p11 Heterotetramer

Phosphoinositide Specificity of and Mechanism of Lipid Domain Formation by Annexin A2-p11 Heterotetramer

Annexin A5 stimulates autophagy and inhibits endocytosis

Fusion of Lamellar Body with Plasma Membrane Is Driven by the Dual Action of Annexin II Tetramer and Arachidonic Acid

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