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Expanding the optogenetics toolkit

October 2018. Controlling individual brain cells using light-sensitive proteins has proven to be a powerful tool for probing the brain's complexities. As this branch of neuroscience has expanded, so has the demand for a diverse palette of protein tools.

A multidisciplinary team from the Howard Hughes Medical Institute's Janelia Research Campus and Goethe University Frankfurt found a new way to engineer these proteins, called rhodopsins. By flipping proteins in the cell membrane upside down, the scientists were able to generate tools with distinct properties, they report 18 October 2018 in the journal Cell. The technique could double the number of proteins available for optogenetics - a technique for manipulating the activity of neurons with light.

To date, scientists have had two main ways to find new proteins for optogenetics. One is by discovering them in nature through genome mining. The other is by gradually mutating proteins until they have desirable features. Each approach has strengths, but also limits in its ability to provide the full suite of characteristics neuroscientists need for increasingly precise experiments.

Inspired by evolution, the Janelia researchers developed a complementary technique for engineering new rhodopsins. In addition to mutation, protein diversity arises in nature when proteins change through recombination - combining protein domains with distinct functions through the reshuffling of genes. Scientists think recombination was critical for the emergence of a subset of proteins that have altered their orientation in the cell membrane through evolution.

Even though flipped proteins exist in nature, conventional wisdom suggests that engineering one is next to impossible. Proteins have shapes finely tuned for their orientation in the membrane, and they usually fail to form functional proteins when researchers try to change them in the lab. Yet when the Janelia researchers mimicked recombination by adding a new protein onto one end of a rhodopsin, it flipped upside down. Not only could the team change the orientation of proteins, but they also found that the new rhodopsins had unique and useful new functions. One, named FLInChR (Full Length Inversion of ChR), started as a rhodopsin that activates neurons. When flipped, it became an inhibitor. The Frankfurt scientists on the team confirmed with a behavioural study, using C. elegans worms expressing FLInChR in muscle cells, that this new opsin variant is a powerful new inhibitor.

The new findings suggests that membrane topology provides a useful additional dimension of protein engineering that may permit a doubling of the optogenetic toolkit. Link to the publication ...

Alexander Gottschalk, Buchmann Institute for Molecular Life Sciences and Institute of Biophysical Chemistry, Riedberg Campus, Goethe University, Frankfurt/Main, Germany, a.gottschalk@em.uni-frankfurt.de


Jennifer Brown, Reza Behnam, Luke Coddington, D. Gowanlock R. Tervo, Kathleen Martin, Mikhail Proskurin, Elena Kuleshova, Junchol Park, James Phillips, Amelie C. F. Bergs, Alexander Gottschalk, Joshua T. Dudman, and Alla Y. Karpova. Expanding the optogenetics toolkit by topological inversion of rhodopsins. Cell. Published online 18 October 2018. doi: 10.1016/j.cell.2018.09.026. Link ...