Annexin A2 heterotetramer: structure and function

Abstract

Annexin A2 is a pleiotropic calcium- and anionic phospholipid-binding protein that exists as a monomer and as a heterotetrameric complex with the plasminogen receptor protein, S100A10. Annexin A2 has been proposed to play a key role in many processes including exocytosis, endocytosis, membrane organization, ion channel conductance, and also to link F-actin cytoskeleton to the plasma membrane. Despite an impressive list of potential binding partners and regulatory activities, it was somewhat unexpected that the annexin A2-null mouse should show a relatively benign phenotype. Studies with the annexin A2-null mouse have suggested important functions for annexin A2 and the heterotetramer in fibrinolysis, in the regulation of the LDL receptor and in cellular redox regulation. However, the demonstration that depletion of annexin A2 causes the depletion of several other proteins including S100A10, fascin and affects the expression of at least sixty-one genes has confounded the reports of its function. In this review we will discuss the annexin A2 structure and function and its proposed physiological and pathological roles.

Figure 1

Domain structure of annexin A2. Annexin A2 is composed to two domains—the amino-terminal domain and carboxyl-terminal domain. The amino-terminal is the site for post-translational modifications (Ser-1–Phe-32) such as acetylation (Ser-1) and phosphorylation (Ser-11, Tyr-23, Ser-25). Additionally it also encompasses the redox reactive cysteine residue (Cys-8) and the nuclear export sequence (NES) (Val-3-Leu-12). The S100A10 binding site is an amphipathic α-helix, with the hydrophobic residues, Val-3, Ile-6, Leu-7 and Leu-10 making contacts with S100A10. The carboxyl-terminal core domain includes four predominantly alpha-helical domains each containing 70 amino acids. This carboxyl-terminal core domain contains binding sites for heparin and RNA, calcium and phospholipid and as well as for F-actin.

Figure 2

Phospholipid binding domain of annexin A2. For simplicity only the fourth domain (IV) of annexin A2, encompassing the five regions of alpha-helix (helix IVA to helix IVE) is presented. This cartoon illustrates the location of the endonexin fold (Arg-272-Arg-283). The calcium and phospholipid binding sites are located in the AB loop connecting helix IVA to helix IVB and also include the distal aspartic acid residue. The * indicates the lysine residues shown to participate in binding PtdIns(4,5)P2.

Figure 3

Experimental model of plasmin regulation by cell surface annexin A2 and S100A10. The heterotetrameric complex consists of two copies of annexin A2 and one copy of the S100A10 dimer. AIIt binds the tissue-plasminogen activator tPA and plasminogen at the carboxyl-terminal lysine residue of the S100A10 subunit. The annexin A2 subunit does not bind tPA or plasminogen but serves as cell surface receptor for S100A10. The urokinase-plasminogen activator is bound to its receptor (uPAR) and forms the uPA/uPAR complex that colocalizes with AIIt. The co-localization of the plasminogen activators and plasminogen by AIIt results in accelerated cleavage of plasminogen into plasmin. Plasmin activates pro-MMPs (matrix metallo-proteases) into active MMPs and further activates pro-uPA into active uPA.

Figure 4

Experimental model of inflammatory pathway regulation by the annexin A2-S100A10 heterotetramer. (a) Plasmin generated by the annexin A2-S100A10 heterotetramer (AIIt) induces the co-localization of membrane-bound annexin A2 and Toll-Like receptor 4 (TLR4), which causes PKC-mediated phosphorylation of cytoplasmic annexin A2 at serines 11 and 25. The phosphorylation of annexin A2 disassembles AIIt allowing the ubiquitation and degradation of S100A10. In addition, tissue-plasminogen activator (tPA) binding to the carboxyl-terminal lysine residue of the S100A10 subunit induces activation of ILK in a CD11b-dependent manner. Both tPA-mediated ILK activation and plasmin (via an unidentified receptor) promote NF-κB nuclear translocation where it induces production of proinflammatory mediators (TNFα, interleukins, etc.). (b) Progastrin binds to monomeric or dimeric annexin A2, but not AIIt, and induces clathrin-mediated endocytosis. Internalization of progastrin activates MAPKs, β-catenin, and nuclear translocation of NF-κB.

Figure 4

Experimental model of inflammatory pathway regulation by the annexin A2-S100A10 heterotetramer. (a) Plasmin generated by the annexin A2-S100A10 heterotetramer (AIIt) induces the co-localization of membrane-bound annexin A2 and Toll-Like receptor 4 (TLR4), which causes PKC-mediated phosphorylation of cytoplasmic annexin A2 at serines 11 and 25. The phosphorylation of annexin A2 disassembles AIIt allowing the ubiquitation and degradation of S100A10. In addition, tissue-plasminogen activator (tPA) binding to the carboxyl-terminal lysine residue of the S100A10 subunit induces activation of ILK in a CD11b-dependent manner. Both tPA-mediated ILK activation and plasmin (via an unidentified receptor) promote NF-κB nuclear translocation where it induces production of proinflammatory mediators (TNFα, interleukins, etc.). (b) Progastrin binds to monomeric or dimeric annexin A2, but not AIIt, and induces clathrin-mediated endocytosis. Internalization of progastrin activates MAPKs, β-catenin, and nuclear translocation of NF-κB.

Figure 5

Functions of annexin A2-S100A10 complex. The schematic diagram summarizes the functions of annexin A2 discussed in the review.