Figure 2. Structures and Ca²⁺-binding properties of synaptotagmins.

A. Canonical domain structures and classification of synaptotagmins. Mammals express 16 synaptotagmins composed of an N-terminal transmembrane region preceded by a short non-cytoplasmic sequence and followed by a variable linker sequence and two C2-domains; in addition, a 17^th related protein called B/K-protein contains the same domain structure but an N-terminal lipid anchor instead of the transmembrane region (see Pang and Südhof, 2010, for a discussion of additional synaptotagmin-related proteins). Eight synaptotagmins bind Ca²⁺ (Syt1, 2, 3, 5, 6, 7, 9, and 10; blue and red); the remaining synaptotagmins do not (black). The eight Ca²⁺-binding synaptotagmins fall into two broad classes that differ in the absence (Syt1, 2, 7 and 9; blue) or presence (Syt3, 5, 6, and 10; red) of disulfide-bonded cysteine residues in their N-terminal sequences. Note that Syt1 and 2 include an N-glycosylated sequence at the N-terminus (indicated by a ‘Y’), and that Syt7 is extensively alternatively spliced in the linker sequence (Han et al., 2004).

B. Atomic structures of the C2A- and C2B-domains of Syt1 containing bound Ca²⁺-ions (red spheres) bound to flexible loops formed by an eight-stranded β-sandwich (from Sutton et al., 1995; Ubach et al., 1999; Fernandez et al., 2001).

C. Structure of the Ca²⁺-binding sites of the Syt1 C2A domain (modified from Fernandez-Chacon et al., 2001). The Syt1 C2A-domain contains three Ca²⁺-binding sites, of which the central two are canonical for all Ca²⁺-binding C2-domains, whereas the third Ca²⁺-site on the left is variably observed in C2-domains, and is absent from the Syt1 C2B-domain. A further Ca²⁺-binding site that localizes to loop1 on the right is observed in some C2-domains, but is absent from Syt1 and is not shown. Loops refer to the flexible sequences on the top of the Syt1 C2-domain sandwich; the structures of some of the side chains are indicated.