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First published online May 28, 2004
doi: 10.1242/10.1242/jcs.01245

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Annexins – unique membrane binding proteins with diverse functions

Institute of Medical Biochemistry, Center for Molecular Biology of Inflammation, University of Münster, von-Esmarch-Str. 56, Münster 48149, Germany

View larger version (25K): [in a new window]   Fig. 1. Molecular structure of annexin A1. Ribbon presentation showing the three-dimensional fold of the C backbone of annexin A1 in the presence (left) or absence (right) of Ca2+ ions (Rosengarth et al., 2001; Rosengarth and Luecke, 2003). The N-terminal domain (residues 1-40) is disordered in the X-ray structure of the Ca2+-bound annexin A1 and integrates into repeat 3 of the folded core domain in the Ca2+-free protein (depicted in yellow in the right-hand structure). Thus, upon Ca2+ binding, the N-terminal helix is expelled from the protein core and most likely becomes accessible for other interactions (Rosengarth and Luecke, 2003). In the Ca2+-bound conformation, the annexin can attach to membranes through its convex (upper) side, with the Ca2+ ions serving a bridging function. Figure kindly provided by Anja Rosengarth (University of California, Irvine).

View larger version (21K): [in a new window]   Fig. 2. Model of membrane domain stabilization mediated by annexin A2. The model takes into account the Ca2+-dependent binding of annexin-A2–S100A10 to acidic phospholipids, which is mediated through the annexin core domain (left). Lateral diffusion could then direct the complex to raft membrane domains rich in cholesterol, glycosphingolipids and certain phosphatidylinositol phosphates, in particular phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2]. This could result in an annexin-A2–S100A10 fraction not requiring external Ca2+ for raft lipid binding. Following this raft recruitment, lateral annexin-annexin interactions, possibly regulated by Ca2+, could lead to the formation of a protein scaffold beneath the membrane and the concomitant clustering of rafts and recruitment of F-actin.

View larger version (19K): [in a new window]   Fig. 3. Potential role of annexin-A2–S100A10 in the transport of plasma membrane channels. Plasma membrane ion channels containing a binding site for S100A10 (e.g. the Ca2+ channel TRPV5 or the sodium channel Nav 1.8) can be directed to the cell surface through a S100A10-mediated interaction with the annexin-A2–S100A10 complex and subsequent membrane binding of the annexin A2 subunits of the complex. This could occur within the biosynthetic pathway or upon recycling of the channels through an endosomal recycling organelle.

View larger version (22K): [in a new window]   Fig. 4. Inhibition of leukocyte extravasation by annexin A1. Directed leukocyte transmigration through activated endothelium (red) into inflamed/infected tissue is mediated by chemoattractant receptors of the FPR family, which are targets of fMLF (left). This directed migration is inhibited in the presence of extracellular annexin A1 and/or N-terminal annexin A1 peptides, which are probably generated at sites of inflammation (right). An interaction of annexin A1 with FPR/FPRLs present on migrating leukocytes can trigger receptor desensitization and/or L-selectin shedding, leading to the observed block in directed leukocyte migration.

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