Nerve cells communicate via electrical signals that travel at high speeds. However, these signals cannot pass across the gaps – called synapses – that separate one nerve cell from the next. Instead, signals pass between nerve cells via molecules called neurotransmitters that are released from the membrane of the first cell and recognized by receptors in the membrane of the next. Prior to being released, neurotransmitters are packaged inside bubble-like structures called vesicles. The synaptic vesicles must fuse with the cell membrane in order to release their contents into the synaptic cleft. Proteins called SNAREs work together with other proteins to allow this membrane fusion to occur rapidly after the electrical signal arrives. Complexin is a synaptic protein that binds tightly to a complex of SNARE proteins to regulate membrane fusion. This protein activates the quick release of neurotransmitters, which is triggered by an increase in calcium ions as the electrical signal reachess the synapse. Complexin also regulates a different type of neurotransmitter release, which is known as “spontaneous release”. The complexin protein is made up of different regions, each of which is required for one or more of the protein’s activities. However, it is not clear how these regions, or domains, interact with SNAREs and other proteins to enable complexin to perform these roles. Choi et al. have now investigated whether the different activities of mammalian complexin are related to the structure that it adopts when it interacts with the SNARE complex. Complexes of SNARE proteins were assembled with one of the SNARE proteins tethered to a surface for imaging. Next, a light-based imaging technique called single molecule Förster resonance energy transfer (or FRET) was used to monitor how complexin interacts with the SNARE complex. This technique allows individual proteins that have been labeled with fluorescent markers to be followed under a microscope and can show how they interact in real-time. Using this approach, Choi et al. showed that complexin could adopt two different shapes or conformations when it binds to the SNARE complex. In one, complexin interacted closely with the SNARE complex so that it made part of the complex change shape. In the other, complexin was able to bridge two SNARE complexes. Complexin can therefore interact with SNARE complexes in different ways by using different regions of the protein. These findings provide insight into how complexin may regulate membrane fusion via the SNARE complex. In the future, single molecule FRET could be used to study other proteins found at synapses and understand the other steps that regulate the release of neurotransmitters.
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