How Does Complexin Stop Synaptic Vesicles from Fusing? - Jeremy Dittman
October 3, 2014 @ Picower Institute for Learning and MemoryÂ
Jeremy Dittman: Cornell University.Â
An intriguing topic in the field of synaptic biology is what mechanisms control vesicle fusion at the synapse. More specifically, do different molecules regulate evoked and spontaneous fusion?Â
Professor Dittman presented a beautiful paper describing different Complexin subunits and their various functions. He started off by describing the different classes of fusion events and mentioning one major question concerning spontaneous fusion:
"Is Spontaneous Fusion Background Noise or....?"
With a brief mention of various proteins known to be acting on the synaptic vesicles (munc13, munc18, synaptotagmin, tomosyn, complexin - binds on groove between synaptobrevin and syntaxin), Professor Dittman described significant papers that described the function of complexin in different animal models.Â
C. elegan - Martin et al 2011
Mice - Kaeser-Woo et al 2012 (Sudhof Lab)
in vitro - Chicka and Chapman 2009
Drosophila - Huntwork and Littleton 2007
3D Structure - Chen et al Neuron 2002
After his brief overview of known complexin function, Dittman began getting into the details. What is known about complexn is that the Central Helix (CH) is required for function at the synapse. Dittman described the function of the AH and CTD, two subunits of Complexin that are NOT highly conserved across animal models.Â
On the CTD, Dittman's hypothesis was that delta_CTD directs complexin to snares. Through various approaches, Dittman demonstrated that there was a nonrandom distribution of the amino acids in the alpha-helix. In particular, delta12 interacts with lipid membrane. CTD acts on the vesicle.Â
On the AH, amino acids were not conserved, but the biochemical properties were maintained such that the stability of the alpha helical structure was maintained. The alpha helix stability led to the stability of the CH. Without AH presence, SNARE complex formation was inhibited.Â
As this is the first of many lectures that I will be writing on, I am uncertain on the accuracy of these findings (I took some spotty notes). What I took fro this lecture, however, was the steps that Dittman took in presenting his research. If there is such a thing as the "perfect paper," his papers might be it. One of the methods he took in his investigation was to replace specific amino acids with similar amino acids that had slightly more affinity or less affinity to the lipid bilayer. In doing so, he was able to show in rescue experiments that changes in amino acid property on the CH and AH domain led to partial or full rescue. This was made beautiful on graphs in ways I cannot describe. I encourage you to read his papers.Â
Martin et al 2011
CTD - Wragg RT Neuron 2013
CTD - Snead D Nature Comm 2014
AH - Giraudo et al Science 2009
AH - Kummel et al NSMB 2011
Tribuch et al eLife 2014
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The Lecture Series focuses on my reflections on talks I go to. They will mostly be on neuroscience but will sometimes venture into other fields. Most of these posts are a scattering of thoughts in my own attempts to understand topics in the field and are by no means completely accurate.Â
