February 07, 2022

This protein can help us think, or it can shred our cells

San Diego – A new study reveals that a protein long known to play a role in communication between cells in the brain is also capable of obliterating cells if left unchecked because of its penchant for twisting and puncturing the cell membranes.

The protein — known as complexin — if left alone is so toxic it can shred cells. Yet, in the brain, a suite of controls makes sure the protein plays nice and helps neurons communicate by aiding in the release of neurotransmitters.

The findings are published Feb. 7 in Nature Structural and Molecular Biology. "We argue that’s the most interesting membrane fusion event in our bodies, because it’s the one that underlies this conversation. It controls remembering and forgetting. It is everything," says Ed Chapman, professor of neuroscience at the University of Wisconsin School of Medicine and Public Health. "Yet to this day, nobody knows just how the proteins involved in this process really work."

In trying to better understand these proteins Chapman's lab and their collaborators discovered the surprising power of complexin. They found that it dramatically bends and reorders membranes. Live videos show the protein pinching off small bubbles of membrane while simultaneously poking holes in them.  Ultrahigh-resolution 3D images produced by the laboratories of Dorit Hanein and Niels Volkmann at the Scintillon Institute in San Diego also revealed, directly through Cryo-EM imaging, that complexin induces the formation of twisting curlicues of broken-apart membranes.

If complexin showed off its full strength in the body, it would shred neurons to bits. “Of all the proteins we’ve looked at, complexin is the only one that dramatically transforms membranes all by itself,” says Chapman. “It must be subject to some pretty serious regulation, or else we’d all be dead.”

In further experiments, the team discovered some of the ways neurons might keep complexin in check. Most of all, the number of complexin proteins that cooperate at any one time appears to be strictly limited. Only in high numbers does complexin ravage cells. It may be that in small, controlled quantities, it simply promotes membrane fusion.

Now that they’ve learned more about how complexin works, the team is eager to continue applying their unique multidisciplinary approach to expanding these discoveries the other proteins essential in transporting neurotransmitters.

This work was supported in part by the National Institutes of Health (grants MH061876, NS097362, P01-GM121203, DP2GM140920, S10-OD012372, P01-GM121203, and R01-AI132378), the national Science Foundation (grant. NSF-DMS1661900 and OCI-1053575.) and the PEW innovation funds 864K625. Chapman is an Investigator of the Howard Hughes Medical Institute. Hanein and Chapman are The Pew Charitable Trusts Innovation Fund Investigators.

Courtney, K.C., Wu, L., Mandal, T. et al. The complexin C-terminal amphipathic helix stabilizes the fusion pore open state by sculpting membranes. Nat Struct Mol Biol (2022). https://doi.org/10.1038/s41594-021-00716-0

Contact: Ed Chapman, chapman@wisc.edu ; Dorit Hanein dorit@scintillon.org; Niels Volkmann niels@scintillon.org