Structure of the first C₂ domain of synaptotagmin I: A novel Ca²⁺/phospholipid-binding fold

C₂ domains are regulatory sequence motifs that occur widely in nature. Synaptotagmin I, a synaptic vesicle protein involved in the Ca²⁺ regulation of exocytosis, contains two C₂ domains, the first of which acts as a Ca²⁺ sensor. We now describe the three-dimensional structure of this C₂ domain at 1.9 Å resolution in both the Ca²⁺-bound and Ca²⁺-free forms. The C₂ polypeptide forms an eight-stranded β sandwich constructed around a conserved four-stranded motif designated as a C₂ key. Ca²⁺ binds in a cup-shaped depression between two polypeptide loops located at the N- and C-termini of the C₂-key motif.