Three-dimensional structure of the synaptotagmin 1 C₂B-domain: Synaptotagmin 1 as a phospholipid binding machine

Synaptotagmin 1 probably functions as a Ca²⁺ sensor in neurotransmitter release via its two C₂-domains, but no common Ca²⁺-dependent activity that could underlie a cooperative action between them has been described. The NMR structure of the C₂B-domain now reveals a β sandwich that exhibits striking similarities and differences with the C₂A-domain. Whereas the bottom face of the C₂B-domain has two additional α helices that may be involved in specialized Ca²⁺-independent functions, the top face binds two Ca²⁺ ions and is remarkably similar to the C₂A-domain. Consistent with these results, but in contrast to previous studies, we find that the C₂B-domain binds phospholipids in a Ca²⁺-dependent manner similarly to the C₂A-domain. These results suggest a novel view of synaptotagmin function whereby the two C₂-domains cooperate in a common activity, Ca²⁺-dependent phospholipid binding, to trigger neurotransmitter release.