Annexins (Lipocortins)

Abstract

The annexins or lipocortins are a multigene family of proteins that bind to acidic phospholipids and biological membranes in a Ca²⁺-dependent manner (Gerke and Moss 2002; Gerke et al. 2005; Raynal and Pollard 1994; Swairjo and Seaton 1994). Annexins are ubiquitous and characterized by an ability to bind to anionic phospholipids at membrane surfaces in response to elevated Ca²⁺. Annexins are amphipathic and distinct from soluble and integral membrane proteins, but share features of both (Kojima et al. 1994; Brisson et al. 1991). Annexins have molecular weights ranging between 30 and 40 kDa (only annexin 6 is 66 kDa) and possess striking structural features. The characteristic annexin structural motif is a 70-amino-acid repeat, called the annexin repeat. Four annexin repeats packed into an α-helical disk are contained within the C-terminal polypeptide core (Gerke and Moss 2002). While all annexins share this core region, aminoterminal domains of annexins are diverse in sequence and length (ranging from 11 to 196) on each annexin member. It is this diversity of N-terminal amino-acid sequence that gives the individual annexins their functional differences and biological activities and appears to differentiate the cellular function and location (Gerke and Moss 2002; Gerke et al. 2005; Raynal and Pollard 1994). Cysteine 198 is relatively conserved in annexins, and three of four cysteines (198, 242, and 315) in annexin A4 are conserved in annexin 3. Phospholipids are suggested to bind via hydrophilic head groups to annexins, and the phospholipid-binding region is proposed to be localized on the convex surface side where calcium-binding sites are located in the crystal structure of annexin 5 (Huber et al. 1990). The calcium- and phospholipid-binding sites are located in the carboxy terminal domains. Some of the annexins bind to glycosaminoglycans (GAGs) in a Ca²⁺- dependent manner. While annexin 2 has specific and high-affinity heparin-binding activity (Kassam et al. 1997), annexin A4 binds to heparin, heparan sulfate and chondroitin sulfate (CS) columns in a Ca²⁺- dependent manner, annexin 5 to heparin and heparan sulfate columns in a Ca²⁺-dependent manner and annexin 6 to heparin and heparan sulfate columns in a Ca²⁺-independent manner and to CS columns in a Ca²⁺-dependent manner (Ishitsuka et al. 1998) (see Table 21.1). Reports suggest that some annexin species may function as recognition elements for L-α-dipalmitoylphosphatidylethanolamine (PE)-derivatized GAGs under some conditions. The crystal structure of several of the annexins has been reported (Favier-Perron et al. 1996; Luecke et al. 1995; Swairjo et al. 1995). It has been established that the annexins are composed of two distinct sides. The convex side faces the biological membrane and contains the Ca²⁺- and phospholipid-binding sites. The concave side faces the cytosol and contains the N and C termini. Although the annexins have been studied mostly as calcium-dependent phospholipid-binding proteins mediating membrane-membrane and membrane-cytoskeleton interactions, annexins A4, A5 and A6 bind also to carbohydrate structures suggesting that these annexin possess lectin-like domains.