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.
Download full-text PDF |
Source |
---|---|
http://dx.doi.org/10.1038/nsmb1056 | DOI Listing |
Cell Biosci
January 2025
Department of Pathology, Xinqiao Hospital, Third Military Medical University, 183 Xinqiao Street, Shapingba District, Chongqing, 400037, PR China.
Background: Tandem C2 domains, nuclear (TC2N) is a protein that has been characterized to contain C2A domain, C2B domain, and a short C-terminus with a WHXL motif. In previous studies, we have uncovered the oncogenic role and mechanisms of TC2N in lung cancer: TC2N achieves this by inhibiting the p53 signaling pathway and activating the NF-kappaB signaling pathway. Beyond that, its precise function in tumorigenesis is not fully understood.
View Article and Find Full Text PDFFEBS Open Bio
January 2025
Institute of Neurophysiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany.
Neurotransmitter release is triggered in microseconds by the two C domains of the Ca sensor synaptotagmin-1 and by SNARE complexes, which form four-helix bundles that bridge the vesicle and plasma membranes. The synaptotagmin-1 CB domain binds to the SNARE complex via a 'primary interface', but the mechanism that couples Ca-sensing to membrane fusion is unknown. Widespread models postulate that the synaptotagmin-1 Ca-binding loops accelerate membrane fusion by inducing membrane curvature, perturbing lipid bilayers or helping bridge the membranes, but these models do not seem compatible with SNARE binding through the primary interface, which orients the Ca-binding loops away from the fusion site.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
January 2025
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390.
Neurotransmitter release is triggered in microseconds by Ca-binding to the Synaptotagmin-1 C-domains and by SNARE complexes that form four-helix bundles between synaptic vesicles and plasma membranes, but the coupling mechanism between Ca-sensing and membrane fusion is unknown. Release requires extension of SNARE helices into juxtamembrane linkers that precede transmembrane regions (linker zippering) and binding of the Synaptotagmin-1 CB domain to SNARE complexes through a "primary interface" comprising two regions (I and II). The Synaptotagmin-1 Ca-binding loops were believed to accelerate membrane fusion by inducing membrane curvature, perturbing lipid bilayers, or helping bridge the membranes, but SNARE complex binding through the primary interface orients the Ca-binding loops away from the fusion site, hindering these putative activities.
View Article and Find Full Text PDFBiophys J
November 2024
Department of Cell Physiology and Molecular Biophysics, Texas Tech University Health Sciences Center, Lubbock, Texas; Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, Texas. Electronic address:
Synaptotagmin-1 (syt1) functions as the Ca-dependent sensor that triggers the rapid and synchronous release of neurotransmitters from neurotransmitter-containing vesicles during neuronal exocytosis. The syt1 protein has two homologous tandem C2 domains that interact with phospholipids in a Ca-dependent manner. Despite the crucial role of syt1 in exocytosis, the precise interactions between Ca, syt1, and phospholipids are not fully understood.
View Article and Find Full Text PDFEBioMedicine
November 2024
The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, 3052, VIC, Australia. Electronic address:
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!