Figure 1. Structure of the annexins. (a) Annexins consist of an N-terminal domain of variable length and a protein core composed of four annexin folds which contain the binding sites for Ca²⁺ and phospholipids. Boxes (a–e) represent helices as observed in the crystal structure of annexin V. Annexin VI is made up of eight annexin folds. Shown here for annexin II, in the N-terminal region, phosphorylation sites and binding sites for targets (S100A10) are present. (b) Structure of annexin V, which, in the presence of phospholipids, binds 10 molecules of Ca²⁺. Modified from Huber et al. (1990) and Swairjo et al. (1995). (Brookhaven Data Base, PDB entry code: 1A8A.)

Figure 2. Typical structure of a C2-domain protein. (a) Ribbon diagram showing the topology of the eight strands of the C2A-domain of synaptotagmin I (left) and the PLC1 (right). Modified from Nalefski and Falke (1996) and Rizo and Sudhof (1998). (Brookhaven Data Base, PDB entry code for PKC (topology I): 1A25 and for PLC1 (topology II): 1DJH.) The loop region is depicted with three Ca²⁺ ions bound. (b) Schematic representation of the topologies found in synaptotagmin I (topology I) and PLC1 (topology II). Strand-numbering corresponds to the order as found in the primary sequence. In both cases, eight strands form the domain, but the geometrical arrangement of the strands is different in the two groups.

Figure 3. EF-hand motif. (a) The three-dimensional arrangement of the EF-hand motif can be simulated by the right hand, with the index finger representing the E-helix (residues 1–10), the bent middle finger symbolizing the Ca²⁺-binding loop (10–21) and the thumb depicting the F-helix (19–29). The geometrical arrangement of the seven oxygen ligands coordinating the Ca²⁺ ion can best be described as a pentagonal bipyramid. Modified from Celio et al. (1996). (b) Crystal structure from EF-domain of PV. Modified from Kretsinger and Nockolds (1973). (c) Coordination of the Ca²⁺ ion in CaM with the seven oxygen ligands (five from side-chains, one from a carbonyl group of the backbone and one from a water molecule). (d) Consensus sequence for the canonical EF-hand domain. The symbol n denotes nonpolar side-chains and the positions X, Y, Z, –Y,–X and –Z provide the oxygen ligand for the Ca²⁺ binding. At position –Y, a carbonyl oxygen bonds to the Ca²⁺ ion. The –X ligand (usually glutamate) binds Ca²⁺ with both oxygen atoms from the carboxylate group (Kawasaki et al., 1998). * Any amino acid; I, isoleucine.

Figure 4. Structure of CaM. (a) In the Ca²⁺-free form, CaM is dumbbell-shaped and the two pairs of EF-hand domains are linked by a flexible tether (Babu et al., 1988). (b) After Ca²⁺ binding, CaM becomes more globular and can wrap around target proteins (e.g. myosin light-chain kinase; Ikura et al., 1992). (Brookhaven Data Base, PDB entry codes: 1CLL and 3CLN.)

Figure 5. Vitamin K-dependent proteins. (a) Structure of the modified amino acid -glutamate (Gla). (b) Picture of prothrombin fragment 1. The peptide is in wire-frame form except for Ala1, Phe5, Leu6 and Val9. Modified from Nelsestuen and Ostrowski (1999). (Brookhaven Data Base, PDB entry code: 2PF2.)