Annexins

Annexins form a family of Ca2 +-binding proteins. There are now over 100 annexins sequenced in 45 species, 12 of which are in humans. Annexins interact with lipids of cell membranes at elevated Ca2 + levels at the periphery. They assemble there to form trimers or hexamers. The hexamer structures then mostly form ion channel transport proteins (Rescher U et al. 2004).

Most annexins can be associated with membrane-related functions in cells. For example, annexins are transported to the surface in apoptotic cells and prevent the immune response. Furthermore, annexins are involved in certain endo- and exocytotic processes, in the organization of membrane domains and in the maintenance and regulation of contacts between membrane and cytoskeleton.

AnxA1: AnxA1 has been shown to be involved in the inward budding of vesicles at late endosomes, thereby facilitating endocytosis and lysosomal targeting of the EGF receptor. Annexin 1 together with other cytokines /TNF-alpha, interferon-gamma) promotes apoptosis of epidermal keratinocytes via the formyl peptide receptor1.
AnxA2, on the other hand, is involved in the regulation of actin dynamics on endosomes and thus in endosome maturation. In addition, AnxA2 has been associated with the regulation of actin rearrangements at the actin-plasma membrane interface during various processes. This plays a role in the pathogenesis of toxic epidermal necrolysis.

AnxA6 and AnxA8: Both annexins are associated with the balancing of late endosomal cholesterol and the regulation of postendosomal trafficking events.

AnxA13b: AnxA13b is another annexin involved in exocytotic membrane trafficking. It mediates the transport of post-Golgi transport vesicles to the apical cell surface in polarized epithelial cells. AnxA2 also has a function in the establishment/stabilization of the apical membrane domain of epithelial cells.

Structurally, annexins can be divided into two separately folded domains: an N-terminal domain of different length and sequence and a conserved C-terminal domain, which is often referred to as the annexin core. Annexin cores consist of four (eight for annexin A6) annexin repeat sequences, i.e. segments 70-80 amino acids long, each comprising four α-helices aligned in parallel. Together, these annexin repeats of the core domain form a structure (slightly curved disk) that harbors Ca2 + and phospholipid binding sites. The annexin core domain can therefore be considered as a peripheral membrane-binding module that associates with the cytosolic side of cell membranes, especially the plasma membrane, through Ca2 + ions bound to type II sites on the convex surface of the annexin disk. The concave surface of the membrane-bound annexin core faces the cytosol and is extended by the N-terminal domain. This N-terminal domain is about 150 amino acids long and differs in sequence between the various annexins. Due to this molecular arrangement, the N-terminal domain of membrane-bound annexins is available for interactions with soluble cytosolic proteins.

Many such interaction partners have now been identified. These mainly include Ca2 +-binding proteins of the EF-hand type, such as members of the S100 protein family. S100-annexin interactions are thought to play a role in membrane fusion by linking two annexin proteins bound to phospholipid membranes. The structures and different interactions of S100-annexin complexes may suggest that there are several possible forms of protein-protein recognition in this process (Rintala-Dempsey AC et al. 2008).

Despite a high degree of sequence and structural similarity, the various annexins appear to differ in their affinity for Ca2 + and phospholipids. It can be assumed that AnxA2 and A6 are more sensitive to Ca2 +, i.e. they bind to acidic phospholipids and cell membranes at lower Ca2 + concentrations than AnxA4 and A5. The graded membrane binding response of different annexins to Ca2 + elevation appears to be important for their function in plasma membrane repair, with more Ca2 + -sensitive annexins acting at an early stage and less sensitive ones acting later, when higher Ca2 + levels are reached.

1. Li YZ et al (2022) Annexin A protein family in atherosclerosis. Clin Chim Acta 531:406-417.
2. McNeil AK et al (2006) Requirement for annexin A1 in plasma membrane repair. In: J Biol Chem 281: 35202-35207.
3. Miwa N et al.(2008) S100-annexin complexes--biology of conditional association. FEBS J 275:4945-4955.
4. Rescher U et al (2004) Annexins--unique membrane binding proteins with diverse functions. J Cell Sci 117:2631-2639.
5. Rintala-Dempsey AC et al (2008) S100-annexin complexes--structural insights. FEBS J 275:4956-4966.