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

Abstract Synaptotagmin 1 probably functions as a Ca 2+ sensor in neurotransmitter release via its two C 2 -domains, but no common Ca 2+ -dependent activity that could underlie a cooperative action between them has been described. The NMR structure of the C 2 B-domain now reveals a β sandwich that exhibits striking similarities and differences with the C 2 A-domain. Whereas the bottom face of the C 2 B-domain has two additional α helices that may be involved in specialized Ca 2+ -independent functions, the top face binds two Ca 2+ ions and is remarkably similar to the C 2 A-domain. Consistent with these results, but in contrast to previous studies, we find that the C 2 B-domain binds phospholipids in a Ca 2+ -dependent manner similarly to the C 2 A-domain. These results suggest a novel view of synaptotagmin function whereby the two C 2 -domains cooperate in a common activity, Ca 2+ -dependent phospholipid binding, to trigger neurotransmitter release.