Differential Interaction of Tomosyn with Syntaxin and SNAP25 Depends on Domains in the WD40 β-Propeller Core and Determines Its Inhibitory Activity

Bielopolski, Noa; Lam, Alice D.; Bar-On, Dana; Sauer, Markus; Stuenkel, Edward L.; Ashery, Uri

doi:10.1074/jbc.m113.515296

Cited by 34 publications

(32 citation statements)

References 53 publications

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“…Interestingly, tomosyn was recently found to be in complexes with both syntaxin monomers and t-SNARE complexes on the plasma membrane. It appears that the tomosyn⅐t-SNARE complex, rather than the tomosyn-syntaxin complex, mediates the inhibitory activity of tomosyn in exocytosis (68), in line with our reconstitution results.…”

Section: Discussionsupporting

confidence: 89%

The N- and C-terminal Domains of Tomosyn Play Distinct Roles in Soluble N-Ethylmaleimide-sensitive Factor Attachment Protein Receptor Binding and Fusion Regulation

Rathore

Gulbranson

et al. 2014

Journal of Biological Chemistry

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Background: Tomosyn regulates vesicle fusion but its mechanism remains incompletely understood. Results: Tomosyn uses its C-terminal domain to arrest SNARE-dependent fusion reactions, whereas its N-terminal domain is required for syntaxin interaction. Conclusion:We have uncovered distinct roles of the N-and C-terminal domains of tomosyn in SNARE binding and fusion regulation. Significance: Our findings shed light upon vesicle transport in the cell.

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Section: Discussionsupporting

confidence: 89%

The N- and C-terminal Domains of Tomosyn Play Distinct Roles in Soluble N-Ethylmaleimide-sensitive Factor Attachment Protein Receptor Binding and Fusion Regulation

Rathore

Gulbranson

et al. 2014

Journal of Biological Chemistry

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“…The regulation of synaptic vesicles contains several steps and requires precise interaction of several specialized proteins, including SNARE complex for membrane fusion and syntaxin for vesicle docking. STXBP5 encodes a syntaxin-binding protein, tomosyn that negatively regulates neurotransmitter release by forming a syntaxin-SNAP25-tomosyn complex (Fujita et al, 1998; Sakisaka et al, 2004; Yizhar et al, 2004; Yamamoto et al, 2009, 2010; Bielopolski et al, 2014). Neuron-specific tomosyn deletion in mouse hippocampal dentate gyrus impairs spatial learning and memory, whereas tomosyn knockdown in dentate gyrus decreases synaptic plasticity of mossy fibers (Barak et al, 2013; Ben-Simon et al, 2015).…”

Section: Synaptic Proteins Regulate Synaptic Function To Maintain Neumentioning

confidence: 99%

A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

Lin

Frei

Kilander

et al. 2016

Front. Cell. Neurosci.

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Autism spectrum disorder (ASD) comprises a range of neurological conditions that affect individuals’ ability to communicate and interact with others. People with ASD often exhibit marked qualitative difficulties in social interaction, communication, and behavior. Alterations in neurite arborization and dendritic spine morphology, including size, shape, and number, are hallmarks of almost all neurological conditions, including ASD. As experimental evidence emerges in recent years, it becomes clear that although there is broad heterogeneity of identified autism risk genes, many of them converge into similar cellular pathways, including those regulating neurite outgrowth, synapse formation and spine stability, and synaptic plasticity. These mechanisms together regulate the structural stability of neurons and are vulnerable targets in ASD. In this review, we discuss the current understanding of those autism risk genes that affect the structural connectivity of neurons. We sub-categorize them into (1) cytoskeletal regulators, e.g., motors and small RhoGTPase regulators; (2) adhesion molecules, e.g., cadherins, NCAM, and neurexin superfamily; (3) cell surface receptors, e.g., glutamatergic receptors and receptor tyrosine kinases; (4) signaling molecules, e.g., protein kinases and phosphatases; and (5) synaptic proteins, e.g., vesicle and scaffolding proteins. Although the roles of some of these genes in maintaining neuronal structural stability are well studied, how mutations contribute to the autism phenotype is still largely unknown. Investigating whether and how the neuronal structure and function are affected when these genes are mutated will provide insights toward developing effective interventions aimed at improving the lives of people with autism and their families.

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“…Tomosyn is a regulatory protein highly expressed in MF-CA3 terminals (Barak et al, 2010; Sakisaka et al, 2008). It is believed that tomosyn interaction with syntaxin (Fujita et al, 1998; Hatsuzawa et al, 2003) and with SNAP-25 (Bielopolski et al, 2014) hinders the formation of the SNARE complex. Tomosyn over-expression led to reduction in P r and inhibition of vesicle priming in neuroendocrine cells and neurons (Fujita et al, 1998; Hatsuzawa et al, 2003; Williams et al, 2011; Yizhar et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

A Combined Optogenetic-Knockdown Strategy Reveals a Major Role of Tomosyn in Mossy Fiber Synaptic Plasticity

et al. 2015

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Summary Neurotransmitter release probability (Pr) largely determines the dynamic properties of synapses. While much is known on the role of presynaptic proteins in transmitter release, their specific contribution to synaptic plasticity is unclear. One such protein, tomosyn, is believed to reduce Pr by interfering with the SNARE complex formation. Tomosyn is enriched at hippocampal mossy fiber-to-CA3 pyramidal cell synapses (MF-CA3), which characteristically exhibit low Pr, strong synaptic facilitation and pre-synaptic PKA-dependent LTP. To evaluate tomosyn's role in MF-CA3 function, we used a combined knockdown (KD)-optogenetic strategy whereby presynaptic neurons with reduced tomosyn levels were selectively activated by light. Using this approach in mouse hippocampal slices we found that facilitation, LTP, and PKA-induced potentiation were significantly impaired at tomosyn-deficient synapses. These findings not only indicate that tomosyn is a key regulator of MF-CA3 plasticity, but also highlight the power of a combined KD-optogenetic approach to determine the role of presynaptic proteins.

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Differential Interaction of Tomosyn with Syntaxin and SNAP25 Depends on Domains in the WD40 β-Propeller Core and Determines Its Inhibitory Activity

Cited by 34 publications

References 53 publications

The N- and C-terminal Domains of Tomosyn Play Distinct Roles in Soluble N-Ethylmaleimide-sensitive Factor Attachment Protein Receptor Binding and Fusion Regulation

The N- and C-terminal Domains of Tomosyn Play Distinct Roles in Soluble N-Ethylmaleimide-sensitive Factor Attachment Protein Receptor Binding and Fusion Regulation

A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

A Combined Optogenetic-Knockdown Strategy Reveals a Major Role of Tomosyn in Mossy Fiber Synaptic Plasticity

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