Close membrane-membrane proximity induced by Ca(2+)-dependent multivalent binding of synaptotagmin-1 to phospholipids.
Synaptotagmin acts as a Ca(2+) sensor in neurotransmitter release through its two C(2) domains. Ca(2+)-dependent phospholipid binding is key for synaptotagmin function, but it is unclear how this activity cooperates with the SNARE complex involved in release or why Ca(2+) binding to the C(2)B domain is more crucial for release than Ca(2+) binding to the C(2)A domain. Here we show that Ca(2+) induces high-affinity simultaneous binding of synaptotagmin to two membranes, bringing them into close proximity. The synaptotagmin C(2)B domain is sufficient for this ability, which arises from the abundance of basic residues around its surface. We propose a model wherein synaptotagmin cooperates with the SNAREs in bringing the synaptic vesicle and plasma membranes together and accelerates membrane fusion through the highly positive electrostatic potential of its C(2)B domain.
Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
Demet
D
Araç
Xiaocheng
X
Chen
Htet A
HA
Khant
Josep
J
Ubach
Steven J
SJ
Ludtke
Masahide
M
Kikkawa
Arthur E
AE
Johnson
Wah
W
Chiu
Thomas C
TC
Südhof
Josep
J
Rizo
D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology*; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D008561:Membrane Fusion / Q000187:drug effects*; D008954:Models, Biological; D008958:Models, Molecular; D010743:Phospholipids / Q000378:metabolism*; D018583:Pliability; D011485:Protein Binding / Q000187:drug effects; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051381:Rats; D013050:Spectrometry, Fluorescence; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism; D050857:Synaptotagmins / Q000737:chemistry / Q000378:metabolism*
D008081:Liposomes; D010743:Phospholipids; D050857:Synaptotagmins; D002118:Calcium