Annexins: linking Ca2+ signalling to membrane dynamics

Key Points

  • Annexins are a multigene family of Ca2+-regulated proteins that are characterized by a unique Ca2+- and membrane-binding module — the annexin core domain. This core domain enables Ca2+-bound annexins to peripherally dock onto membranes that contain negatively charged phospholipids.

  • Each annexin contains a second, highly varible region — the N-terminal interaction domain. It harbours binding sites for cytoplasmic protein ligands that can be targeted to membranes through the annexin-core-mediated phospholipid interaction.

  • Membrane-bound annexins can form lateral self-assemblies that affect the mobility and organization of membrane lipids. Such activities probably regulate membrane-related processes like membrane-domain organization and membrane transport in endocytosis and exocytosis.

  • Interfering with intracellular annexin function, by overexpressing mutants or by using RNA-interference-mediated downregulation, has different effects depending on the annexin being targeted. These include effects on actin assemblies at cellular membranes, the organization of endosomal subcompartments, Ca2+-regulated exocytosis and midbody formation during cytokinesis.

  • Some annexins can also occur extracellularly and can have functions outside cells. Their release is not fully understood, but probably follows non-classical secretion pathways.

  • Extracellular annexin functions that have been substantiated by mouse knockout models are anti-inflammatory and fibrinolytic activities. These are probably mediated through specific cell-surface interactions with chemoattractant receptors on cells of the immune system and key enzymes of the fibrinolytic cascade, respectively.

Abstract

Eukaryotic cells contain various Ca2+-effector proteins that mediate cellular responses to changes in intracellular Ca2+ levels. A unique class of these proteins — annexins — can bind to certain membrane phospholipids in a Ca2+-dependent manner, providing a link between Ca2+ signalling and membrane functions. By forming networks on the membrane surface, annexins can function as organizers of membrane domains and membrane-recruitment platforms for proteins with which they interact. These and related properties enable annexins to participate in several otherwise unrelated events that range from membrane dynamics to cell differentiation and migration.

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Figure 1: Annexin structure.
Figure 2: Annexin assemblies on membranes.
Figure 3: The regulation of membrane–actin interactions by annexin A2.
Figure 4: Annexins in membrane organization and trafficking.
Figure 5: Annexins have specialized extracellular roles.

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Acknowledgements

We thank our colleagues who provided unpublished information and materials that were used in the figures, and apologize to all those researchers whose work could not be discussed owing to space limitations. Work in the authors' laboratories is supported by: the Deutsche Forschungsgemeinschaft, the Interdisciplinary Center for Clinical Research of the Münster Medical School, and the European Union (V.G.); the National Institutes of Health (C.E.C.); and the Wellcome Trust, the Medical Research Council and Fight for Sight (S.E.M.).

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DATABASES

Prosite

C2-domain

EF-hand

Swiss-Prot

annexin A1

annexin A2

annexin A4

annexin A5

annexin A6

annexin A7

annexin A10

annexin A11

annexin A13

annexin B12

NEX-1

sorcin

S100A6

S100A10

S100A11

FURTHER INFORMATION

Volker Gerke's laboratory

Glossary

HYDRA ANNEXIN

Annexin B12 is the predominant annexin in the freshwater cnidarian Hydra vulgaris, and has been the prototype for biophysical studies on annexin insertion into phospholipid bilayers.

EF-HAND SUPERFAMILY

The largest family of Ca2+-binding proteins, which is exemplified by calmodulin. The family members share a structural helix–loop–helix motif — the EF hand — that forms the Ca2+-binding site.

S100 PROTEIN

A family of 1014–kDa, EF-hand-containing Ca2+-binding proteins, which transmit Ca2+-dependent cell-regulatory signals.

PLECKSTRIN-HOMOLOGY-DOMAIN PROTEIN

Proteins that contain a pleckstrin-homology domain, which is a conserved motif that is most frequently associated with binding to inositol phospholipids.

LIPID MICRODOMAIN

A localized membrane region that differs from the surrounding membrane in its lipid composition and order.

LIPID RAFT

Lateral lipid aggregates that are rich in cholesterol and sphingolipids, and are thought to occur in cellular membranes. These lipid microdomains are resistant to solubilization by non-ionic detergents and probably resemble the liquid-ordered domains that are found in model membranes.

CYTOKINESIS

The final stage of the cell-division cycle, in which two daughter cells become separated by the central spindle.

MIDBODY

A dense protein matrix that forms at the midpoint of the central spindle during cytokinesis. Midbody proteins, of which annexin A11 is one, are required for cleavage-furrow formation and the final separation of daughter cells by abscission.

P6 OR P3

Space groups that define crystal lattices with sixfold and threefold axes of symmetry, respectively.

NUCLEOPLASM

The part of the nucleus that is contained by, but is distinct from, the nuclear envelope.

HYDROXYAPATITE

A crystalline form of calcium phosphate that is present in the matrix of bone.

CHROMAFFIN GRANULES

The secretory vesicles of the adrenal medulla. They contain noradrenaline or adrenaline, a number of biologically active peptides and high concentrations of ATP and ascorbic acid. The name is derived from the histological observation that the vesicles are readily stained by chromium salts.

ARACHIDONIC ACID

A highly unsaturated, long-chain fatty acid (20 carbon atoms: 4 double bonds) that is often found at the sn-2 position of the glycerol backbone of membrane phospholipids. It is typically released by phospholipase action in stimulated cells, which allows it to function as a membrane fusogen or as the precursor of active signalling molecules such as the prostaglandins and leukotrienes.

SNARE PROTEINS

(soluble N-ethylmaleimide-sensitive fusion protein (NSF) attachment protein receptor proteins). Integral membrane proteins in vesicle or cell-surface membranes that interact with one another during membrane fusion. The name is derived from the role of these proteins as receptors for a cytosolic protein, NSF, that is essential for organelle trafficking steps that involve membrane fusion.

NON-ERYTHROID SPECTRIN

An isoform of spectrin that is sometimes also called fodrin and is expressed in cells other than erythrocytes.

GLUCOCORTICOIDS

A class of steroid hormones with a potent anti-inflammatory activity.

NEUTROPHIL EXTRAVASATION

The processs by which neutrophils (polymorphonuclear leukocytes) leave a blood vessel.

PERITONITIS

Inflammation of the peritoneum (the membrane that lines the abdominal cavity and digestive organs of vertebrates).

ACUTE-PHASE REACTION

The defense reaction of an organism to infectious or toxic agents, which helps to restrict organ damage through the cytokine-induced production of protective acute-phase proteins such as complement-reactive and serum-amyloid protein.

JURKAT T-LYMPHOCYTES

A commonly used cell line that is derived from an acute lymphoblastic leukaemia of T-cell origin.

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Gerke, V., Creutz, C. & Moss, S. Annexins: linking Ca2+ signalling to membrane dynamics. Nat Rev Mol Cell Biol 6, 449–461 (2005). https://doi.org/10.1038/nrm1661

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