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NATURE MEDICINE ESSAY a Figure 5 a Later Model of the Vesicle Fusion Complex

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NATURE MEDICINE ESSAY a Figure 5 a Later Model of the Vesicle Fusion Complex LASKER MEDICAL BASIC RESEARCH AWARD ESSAY In search of the molecular mechanism of intracellular membrane fusion and neurotransmitter release Richard H Scheller Along with the honor of receiving the Albert into the nerve ending, and this triggers the Lasker Basic Medical Research Award, I wel- fusion of the synaptic vesicle membrane with come the opportunity to reflect on a number the presynaptic membrane and transmitter of discoveries that I have been involved in. My Recycling release. The membrane then recycles, resulting Synaptic vesicle goal is to show how a series of ideas evolved vesicles in new vesicles for another round of release1. from simple models to more complex hypoth- Clathrin Essentially nothing was known about the eses resulting in the understanding, in molecu- Membrane molecular mechanisms that governed this pro- fusion lar detail, of a complex biological process. cess. I remembered that the synaptic vesicles It is likely that all scientists or maybe even were studied from marine rays and that the most people have wondered where thoughts vesicles had been purified from the electric come from, how memory works or how it is organ of these interesting animals. In fact, a Figure 1 The mechanism of neurotransmitter that we have feelings and emotions. These release and recycling. Vesicles dock at the colleague at the University of California–San questions had fascinated me since my earliest presynaptic membrane and, upon calcium entry Francisco, Reg Kelly, had made an antibody days as a scientist. Specifically, how could I, a into the terminal, fuse with the presynaptic against purified vesicles2. My idea was that we molecular biologist and biochemist, contrib- plasma membrane, releasing neurotransmitter1. could screen the expression library that we had ute to understanding how the brain works? I made to clone the agrin cDNA with the anti- was lucky enough to stumble upon the per- Neuroscience Department at Stanford, and we body raised against purified vesicles and that fect situation to begin a career dedicated to struck up a collaboration to better understand this should result in cDNA clones encoding understanding these problems. As a postdoc, the development of the neuromuscular junc- proteins of the vesicle, some of which must be I had the great fortune to work at Columbia tion. McMahon’s lab had characterized a pro- involved in transmitter release. A postdoc (Bill University’s College of Physicians and Surgeons tein he named agrin, which has a critical role in Trimble), a graduate student (Jim Campenelli) with Richard Axel and Eric Kandel. We applied organizing the acetylcholine receptors beneath Synaptic the relatively new techniques of molecular the presynaptic nerve terminal. He had raised vesicle membrane Synaptotagmin biology to problems in neuroscience work- an antibody against the protein and deter- VAMP ing together on the egg-laying behavior of the mined a portion of the amino acid sequence. marine snail Aplysia californica. After a num- To clone the agrin gene, we made an expression ber of fun discoveries, I became an alumnus cDNA library from neurons of the electric lobe of what should now be called the ‘Columbia of the marine ray, Torpedo californica, the spe- School of Neuroscience’ owing to the promi- cies used to purify agrin. nence of ideas that have originated from this At the same time, I began thinking about Syntaxin institution. other problems in neuroscience, and for me, Research in my laboratory in the the mechanism of neurotransmitter release at Department of Biological Sciences at Stanford the presynaptic nerve terminal was particularly University began by continuing our work on interesting. Owing to the work of many who Calcium channel neuropeptides in Aplysia. Along the way, I preceded me, a general outline of the cellular met Jack McMahon, a faculty member in the process was quite well understood (Fig. 1). Ca2+ Classic electron microscopic studies had estab- Figure 2 An initial model of the vesicle fusion Richard H. Scheller is at Genentech Research and lished that the transmitter-containing vesicles complex. VAMP-1 and synaptotagmin on the Early Development, 1 DNA Way, San Francisco, are stored at a region called the active zone. synaptic vesicle membrane interact with syntaxin California, USA. When the action potential invades the termi- on the plasma membrane, which associates in e-mail: [email protected] nal, channels open, allowing calcium to flow turn with the calcium channel4. NATURE MEDICINE VOLUME 19 | NUMBER 10 | OCTOBER 2013 xiii ESSAY and transmitter release upon calcium influx. Synaptotagmin a-SNAP It was also at this time that another soluble factor known to be important in exocytosis VAMP in yeast, called sec1, was added to the picture. Our group at Stanford and Thomas Südhof’s group at the University of Texas Southwestern SNAP-25 n-sec1 7S NSF showed that neuronal Sec1 (n-sec1) bound Syntaxin syntaxin. We showed biochemically and using crystallographic methods that the conforma- tion of syntaxin bound to n-sec1 was incom- 7 ADP + P ATP patible with SNARE complex formation . We i referred to this as the closed conformation of syntaxin and proposed that conformational changes lead to the opening of syntaxin before initiation of the SNARE complex formation. Hugh Pelham next posed the question of 20S whether the SNARE complex formed a heli- cal bundle in a parallel or antiparallel fash- Figure 3 Model of the membrane fusion reaction. A series of assembly and disassembly reactions was proposed to mediate membrane fusion and vesicle targeting specificity6. ion. A parallel formation might result in the actual fusion of the membranes, whereas an antiparallel organization would suggest that and I did the screen and identified a number hypothesis, which postulates that families of the complex was more important in docking of positive clones. Trimble went on to char- SNARE proteins decorate membrane com- the vesicle at the acceptor membrane (Fig. 4). acterize one of the positive clones, which we partments and that the specificity of membrane Using fluorescence resonance energy transfer called vesicle-associated membrane protein-1 fusion is achieved by the formation of protein studies, an MD-PhD student, Richard Lin, (VAMP-1)3. complexes5. So, VAMP-1 turned out to be the showed a parallel organization8, which was Another postdoc, Mark Bennett, and an first vesicle SNARE (v-SNARE), and syntaxin also seen at higher resolution in the crystal MD-PhD student, Nicole Calakos, then joined was the first target SNARE (t-SNARE). structure obtained by Reinhard Jahn and Axel our effort. They immunoprecipitated detergent- This led to a collaboration between Brunger9. This resulted in the general model solubilized membranes from rat brain with an Rothman’s group and my own lab, which of membrane fusion that we now know to be antibody against synaptotagmin (then called resulted in the model shown in Figure 3. The correct (Fig. 5a)8. The SNARE pairing drives p65), a protein we now know to be the cal- idea was that VAMP-1 and synaptotagmin, membrane fusion, a-SNAP and NSF dissoci- cium sensor for neurotransmitter release. We another vesicle protein, bind SNAP-25 and ate, and then the SNARE complex disassembles isolated a 35-kDa protein and characterized syntaxin on the plasma membrane; we called to allow recycling. it by determining a portion of the amino acid this the 7S complex. After adding a-SNAP, At this point, though, the model had very lit- sequence and cloning the cDNA. We named we showed that synaptotagmin was displaced tle experimental support. In my lab, a graduate this protein syntaxin4. Interestingly, syntaxin, from the complex, and, upon addition of NSF, student, Yu Chen, and a postdoc, Suzie Scales, unlike VAMP-1, was largely localized to the a larger complex formed, which we called the decided to investigate the model in PC12 cells plasma membrane. This was something we 20S complex. Upon ATP hydrolysis, not only that had been ‘cracked open’. One could add were hoping to find because this established did NSF and a-SNAP dissociate from the com- back cytosol and ATP in a priming step and a molecular link between the pre- and post- plex, but also the SNARE complex itself disas- trigger release of radioactive norepinephrine synaptic membranes. An initial model of these sembled6. with the addition of calcium10. But how could interactions is shown in Figure 2. At the time, I knew this could not be the full fusion reac- one manipulate exocytosis if the endogenous we felt that these molecules and their interac- tion; calcium triggered transmitter release so SNAREs were present in this system? In the tions had to be important in the release pro- rapidly that there was not enough time for ATP intervening years, it had been shown that cess, but we did not know how. We suggested hydrolysis and complex disassembly to take the clostridial and botulinum neurotoxins that these proteins formed a scaffold for place. To reconcile this, I proposed an inter- cleaved the SNARE proteins and that this was assembly of the soluble factors a-SNAP and mediate step in the process (shown in brackets their mechanism of action. By cleaving one N-ethylmaleimide–sensitive factor (NSF) as in Fig. 3) that would lead to membrane fusion of the four coils of the SNARE complex with these molecules were known to be involved in vesicle trafficking and membrane fusion from a b studies in yeast and mammalian species4. Sure enough, James Rothman’s group showed that VAMP-1, syntaxin and a third pro- tein, synaptosomal protein of 25 kDa (SNAP- 25), bound a column with a-SNAP attached and that the three proteins were released when trans cis 5 ATP was hydrolyzed by NSF . At this time, the Figure 4 The two possible engagements of SNARE coils suggested different functions.
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