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Syntaxin Clustering and Optogenetic Control for Synaptic Membrane Fusion

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Syntaxin Clustering and Optogenetic Control for Synaptic Membrane Fusion Perspecve Syntaxin Clustering and Optogenetic Control for Synaptic Membrane Fusion Miaoling Li 1,†, Teak-Jung Oh 2,†, Huaxun Fan 2,†, Jiajie Diao 3 and Kai Zhang 2, 1 - Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan 646000, China 2 - Department of Biochemistry, University of Illinois at Urbana–Champaign, Urbana, IL 61801, USA 3 - Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA Correspondence to Jiajie Diao and Kai Zhang:Correspondence to: J. Diao, Vontz Center for Molecular Studies, 3125 Eden Avenue, ML 0521, Cincinnati, OH 45267, USA.Correspondence to: K. Zhang, 600 South Mathews Avenue, 314 B Roger Adams Laboratory, Urbana, IL 61801, USA. [email protected], [email protected] https://doi.org/10.1016/j.jmb.2020.07.005 Abstract Membrane fusion during synaptic transmission mediates the trafficking of chemical signals and neuronal communication. The fast kinetics of membrane fusion on the order of millisecond is precisely regulated by the assembly of SNAREs and accessory proteins. It is believed that the formation of the SNARE complex is a key step during membrane fusion. Little is known, however, about the molecular machinery that mediates the formation of a large pre-fusion complex, including multiple SNAREs and accessory proteins. Syntaxin, a transmembrane protein on the plasma membrane, has been observed to undergo oligomerization to form clusters. Whether this clustering plays a critical role in membrane fusion is poorly understood in live cells. Optogenetics is an emerging biotechnology armed with the capacity to precisely modulate protein–protein interaction in time and space. Here, we propose an experimental scheme that combines optogenetics with single-vesicle membrane fusion, aiming to gain a better understanding of the molecular mechanism by which the syntaxin cluster regulates membrane fusion. We envision that newly developed optogenetic tools could facilitate the mechanistic understanding of synaptic transmission in live cells and animals. © 2020 Elsevier Ltd. All rights reserved. Introduction synaptobrevin 2), whereas the t-SNARE proteins include syntaxin-1A and SNAP-25 (synaptosomal- Synaptic vesicle exocytosis mediates neuronal associated protein, 25 kDa) [6]. communication by regulating synaptic transmission In vivo studies demonstrated that the formation of through membrane fusion, protein trafficking [1], and SNARE complex during fast exocytosis completes neurotransmitters release [2]. Defective synaptic within a millisecond [7]. To intuitively understand the vesicle exocytosis could lead to neurodegenerative molecular mechanisms of membrane fusion, diseases [3]. Synaptic vesicle exocytosis is precisely researchers confirmed that SNARE complex and regulated by the coordination of calcium and a additional accessory proteins play a synergistic role group of proteins called SNAREs (soluble N-ethyl- in the regulation of the fusion pathway in vivo [8]. maleimide sensitive factor attachment protein re- Although recently developed single-vesicle fusion ceptors) [4,5]. SNARE proteins are the core assays [9–24] provides improved ways to track component of the exocytosis machinery and reside synaptic membrane fusion at the single-vesicle level either in the presynaptic vesicles (v-SNARE) or the [25,26], it remains challenging to probe the exact targeted plasma membrane SNARE proteins (t- molecular mechanism underlying the release of SNARE). The v-SNARE protein consists of VAMP2 neurotransmitters from synaptic vesicles [27]. A (vesicle-associated membrane protein 2, also called counting list of accessory proteins includes the 0022-2836/© 2020 Elsevier Ltd. All rights reserved. Journal of Molecular Biology (2020) 432, 4773-4782 4774 Optical control of syntaxin for membrane fusion assembly proteins SM (Sec1/Munc18-like proteins), the disassembly factors NSF (N-ethylmaleimide sensitive factor), complexin (a clamp activator), synaptotagmin (a Ca2+ sensor) [4,28]. Together with SNARE proteins, these accessory proteins regulate calcium-triggered fast membrane fusion and exocytosis. What remains unclear is the molecular machinery to initiate the assembly of the large pre-fusion protein complex (Figure 1). The emerging idea is that the configuration and distribution of syntaxin, one of the t-SNARE proteins that localize on the target membrane, could mediate the assembly of a pre-fusion complex [29]. As discussed in detail below, syntaxin could oligomerize and form Figure 1. Schematic of protein cluster-induced forma- nanodomains in the plasma membrane [30], although tion of the pre-fusion superstructure for effective fusion. direct evidence has yet been available to prove that SNAREs are classified according to their compartment syntaxin clustering initiates calcium-triggered, fast distribution as v-SNAREs (in transport vesicles), including membrane fusion either in vitro or in vivo.Inthis synaptobrevin 2 (also called vesicle-associated mem- perspective, we briefly review the formation, dynamics, brane protein 2, VAMP2), and t-SNAREs (in the target function and influencing factors of syntaxin cluster membranes) that composed of SNAP-25 and syntaxin-1A. These three SNARE components can form a ternary during vesicle fusion, and proposed to use photoacti- “ vatable protein-based optogenetics to kinetically complex in a 1:1:1 ratio via the association of their SNARE motifs,” which assemble into a four-helix bundle. The manipulate clustering of syntaxin during vesicle fusion. accessory proteins, including complexin (a clamp activa- It is our expectation that optogenetics could provide tor), synaptotagmin (a Ca2+ sensor), Munc18, and constructive insights into the molecular mechanism Munc13, form a basic interaction module with individual underlying membrane and protein trafficking during SNARE complexes. synaptic transmission. clusters may have distinct functions depending on Dynamic organization of syntaxin on the the size and spatial distribution. For example, STED plasma membrane super-resolution imaging on Drosophila neuro- muscular junctions showed that larger syntaxin Syntaxin is a membrane-anchored protein that plays clusters are more abundant and stable at active a central role in membrane fusion. It contains a zones. Larger clusters could possess a higher cytosolic domain and a type II single-transmembrane capability for vesicle docking, whereas the smaller C-terminal domain. The N-terminal Habc domain of clusters may serve as a reservoir to maintain the syntaxin is believed to interact with Munc18, while the balance of syntaxin distribution between large and SNARE domain can form a four-helix-bundle with small clusters [39]. These results suggest that the SNAP-25 and VAMP2 for membrane fusion (Figure 1). homologous oligomerization of syntaxin proteins Results from super-resolution imaging indicate that plays an essential role in vesicle fusion [40]. syntaxin could undergo a dynamic equilibrium between Super-resolution imaging further unveiled the size clustering and freely diffusive states in the plasma and density of the syntaxin cluster in mammalian membrane [30]. Enhanced clustering causes reduced cells. For example, STED fluorescence microscopy mobility of syntaxin [31,32]. Overexpression of syntaxin resolved that the density of endogenous syntaxin increases the number rather than the size of nanoclus- clusters in PC12 cells is 19.6 clusters/μm2 [30], or ters [33]. Syntaxin could oligomerize via the transmem- 9000 syntaxin clusters per cell. Quantitative immu- brane domain [34] or the cytoplasmic domain [35]. The nostaining estimated the total number of syntaxin per balance between the assembly and disassembly of cell is 830,000, indicating that each cluster contains syntaxin clusters could play a crucial role during about 90 syntaxin molecules. Considering the synaptic transmission [36]. average diameter of the clusters is about 50– Syntaxin clustering could help vesicle tethering 60 nm (resolved by STED), it is expected that and docking prior to membrane fusion. Indeed, it has syntaxins are densely packed in the cluster. This been shown that syntaxin, together with the acces- estimate remains consistent with another study, sory protein Munc18, recruits secretory vesicles to which demonstrated that the density of syntaxin the docking site on the plasma membrane [37]. It is ranged from 540 molecules/μm2 [121]to2000 likely that the Habc-domain of syntaxin mediates molecules/μm2 in PC12 cells [41]. both cluster formation and vesicle docking because Syntaxin clusters coordinate with secretory vesi- both processes slowed down upon overexpression cles by presenting the docking sites for secretory of the Habc domain [38]. In addition, syntaxin granules in the plasma membrane. Moreover, Optical control of syntaxin for membrane fusion 4775 syntaxin clusters are able to assemble reversibly at additional opening is induced upon Ca2+ entry. It the sites of the granule. However, docking of means that one of the transitions is directly induced by granules on syntaxin could be intermittent because depolarization, and an additional transition is involved syntaxin clusters were also found at sites where in the juxtamembrane region of syntaxin [50]. there are no granules [37]. Furthermore, syntaxin clustering at granules requires Munc18-syntaxin The SNARE motif is essential for the formation binding
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