Structure of human synaptotagmin 1 C2AB in the absence of Ca2+ reveals a novel domain association.
Release of neurotransmitter from synaptic vesicles requires the Ca2+/phospholipid-binding protein synaptotagmin 1. There is considerable evidence that cooperation between the tandem C2 domains of synaptotagmin is a requirement of regulated exocytosis; however, high-resolution structural evidence for this interaction has been lacking. The 2.7 A crystal structure of the cytosolic domains of human synaptotagmin 1 in the absence of Ca2+ reveals a novel closed conformation of the protein. The shared interface between C2A and C2B is stabilized by a network of interactions between residues on the C-terminal alpha-helix of the C2B domain and residues on loops 1-3 of the Ca2+-binding region of C2A. These interactions alter the overall shape of the Ca2+-binding pocket of C2A, but not that of C2B. Thus, synaptotagmin 1 C2A-C2B may utilize a novel regulatory mechanism whereby one C2 domain could regulate the other until an appropriate triggering event decouples them.
Fuson
Kerry L
KL
Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, Texas 77555, USA.
Montes
Miguel
M
Robert
J Justin
JJ
Sutton
R Bryan
RB
D000595:Amino Acid Sequence; D002118:Calcium / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D050863:Synaptotagmin I / Q000737:chemistry*
D050863:Synaptotagmin I; D002118:Calcium