Figure 2
Figure 2. Schematic representation of the ANXA2 heterotetramer on the cell surface. ANXA2 belongs to the annexin family of phospholipid and calcium-binding proteins. Annexins bind to anionic phospholipids in a calcium (Ca2+)–dependent manner. All annexins share a conserved domain of 4 repeat sequences ∼ 70 residues long composed of 5 α-helices containing several Ca2+ binding sites. Within the AIIt heterotetrameric complex, ANXA2 is a planar, curved molecule with opposing convex and concave sides. The convex side faces the cellular membrane and contains the Ca2+ and phospholipid binding sites, whereas the concave side faces away from the membrane and contains both the N- and C-terminal regions of ANXA2. The N-terminus of ANXA2 contains the binding site for S100A10, a reactive cysteine residue, phosphorylation sites at Tyr 23 and Ser 14, and a nuclear export signal, whereas the C-terminus contains a reactive cysteine residue and binding sites for F-actin, phospholipid, fibrin, and heparin. S100A10 is a 10-kDa protein containing an N-terminal and a C-terminal EF hand separated by a rather unstructured linker region. One of the main features of S100A10 is the presence of a C-terminal lysine residue that forms a binding site for tPA and plasminogen. AIIt, the predominant form of ANXA2 and S100A10 on the cell surface, is composed of 2 molecules of ANXA2 linked together by a dimer of S100A10. The S100A10 dimer of AIIt is positioned in the center, with an ANXA2 molecule on each side. The first 10 amino acids of ANXA2 form an α-helix, which lies in a hydrophobic cleft formed by loop L2 and helix HIV of one molecule of S100A10 and helix HI of the other S100A10. The ANXA2 binding site on the S100A10 dimer primarily encompasses residues in the C-terminal region extending beyond the second EF hand. The binding of tPA and plasminogen to the complex occurs on the C-terminal lysine of the S100A10 subunit. Removal of the C-terminal lysine results in a heterotetrameric complex that fails to bind tPA and plasminogen and also fails to stimulate tPA-dependent plasminogen activation.29,52

Schematic representation of the ANXA2 heterotetramer on the cell surface. ANXA2 belongs to the annexin family of phospholipid and calcium-binding proteins. Annexins bind to anionic phospholipids in a calcium (Ca2+)–dependent manner. All annexins share a conserved domain of 4 repeat sequences ∼ 70 residues long composed of 5 α-helices containing several Ca2+ binding sites. Within the AIIt heterotetrameric complex, ANXA2 is a planar, curved molecule with opposing convex and concave sides. The convex side faces the cellular membrane and contains the Ca2+ and phospholipid binding sites, whereas the concave side faces away from the membrane and contains both the N- and C-terminal regions of ANXA2. The N-terminus of ANXA2 contains the binding site for S100A10, a reactive cysteine residue, phosphorylation sites at Tyr 23 and Ser 14, and a nuclear export signal, whereas the C-terminus contains a reactive cysteine residue and binding sites for F-actin, phospholipid, fibrin, and heparin. S100A10 is a 10-kDa protein containing an N-terminal and a C-terminal EF hand separated by a rather unstructured linker region. One of the main features of S100A10 is the presence of a C-terminal lysine residue that forms a binding site for tPA and plasminogen. AIIt, the predominant form of ANXA2 and S100A10 on the cell surface, is composed of 2 molecules of ANXA2 linked together by a dimer of S100A10. The S100A10 dimer of AIIt is positioned in the center, with an ANXA2 molecule on each side. The first 10 amino acids of ANXA2 form an α-helix, which lies in a hydrophobic cleft formed by loop L2 and helix HIV of one molecule of S100A10 and helix HI of the other S100A10. The ANXA2 binding site on the S100A10 dimer primarily encompasses residues in the C-terminal region extending beyond the second EF hand. The binding of tPA and plasminogen to the complex occurs on the C-terminal lysine of the S100A10 subunit. Removal of the C-terminal lysine results in a heterotetrameric complex that fails to bind tPA and plasminogen and also fails to stimulate tPA-dependent plasminogen activation.29,52 

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