How Can We Control Proteins with Light?

Overview: Minimally Disruptive Optical Control of Protein Tyrosine Phosphatase 1B

Optogenetics is a flashy new field boasting the development of light-directed mind control. Scientists have learned that we can use light (instead of the neural signal usually required) to get neurons to react, and doing so has led to experiments where scientists can shine light of a certain wavelength on a mouse, inducing it to only run in circles. While this sort of thing requires genetic engineering, it does allow you a precise way to control a particular set of cells, and is theoretically possible to use on larger mammals – including humans.

But optogenetics has another application, one with less shock value. Researchers are using optogenetic tools to manipulate individual cells and proteins so that we can better understand their basic science. Current molecular biology techniques to understand a particular enzyme might involve knocking it out of the genome and observing the results. It’s an on/off switch for you to compare 100% either way. Optogenetic tools, on the other hand, would allow you to study individual enzymes along a gradient of function, as it transitions into light or dark states.

You can move these applications beyond ‘basic science’ discovery. What if we use these methods to better understand proteins associated with cancer? Diabetes? Alzheimer’s? There are direct medical applications to the sheer discovery of how these proteins work and how they affect the biochemical reactions they catalyze. So we are talking about tools that can eventually lead to the development of more specific drugs.

Proteins, after all, are complex things. They have four levels of organization, which only begins with the amino acid sequence encoded in the DNA. After that you see the protein organizing into alpha-helices or beta-sheets, and then folding that determines function. This is determined by intermolecular forces like hydrogen bonding, disulfide bonding, and hydrophobic/hydrophilic interactions between the amino acids and larger structures of the protein. Finally, all these organized features can combine with other three-dimensional proteins into quaternary level organization, where multiple proteins join to form a larger one.

This is the world of proteins, and it is not completely understood. So we can design chimeras – hybrids of two proteins – to better understand how they work. The scientists of today’s paper joined a protein tyrosine phosphatase (PTP) with a light-reacting protein, and then altered different parts of their new chimera to see how its behavior changed.

Why pick these two proteins? PTP is a high-priority protein involved in cell signaling and regulation and closely connected to diabetes, obesity, and cancer. Thus, better understanding how this protein works can help us find new drugs for treating such diseases. We can better understand it by using optogenetic tools, but PTP does not, by itself, respond to light. You can make that happening by engineering a chimera – attach LOV2, the light-sensitive domain of another protein (a protein related to phototropism in plants) and now, you’ve made PTP light-sensitive as well.

The scientists continued fine-tuning their system, and ended up confirming that their engineering enzyme works. It yields tyrosine phosphate activity that can be controlled with light. From a bird’s-eye view, their efforts resulted in a selective, precise tool for analyzing medically impactful biochemical activity. In the next installment of this two-part series, we’ll dig deeper into what kinds of hypotheses they had and how they tested them.

References

Hongdusit, A., Zwart, P. H., Sankaran, B., & Fox, J. M. (2020). Minimally disruptive optical control of protein tyrosine phosphatase 1B. Nature Communications, 11(1). https://doi.org/10.1038/s41467-020-14567-8

Further Reading

Kim, B., & Lin, M. Z. (2013). Optobiology: Optical control of biological processes via protein engineering. Biochemical Society Transactions, 41(5), 1183–1188. https://doi.org/10.1042/BST20130150.Optobiology

Repina, N. A., Rosenbloom, A., Mukherjee, A., Schaffer, D. v., & Kane, R. S. (2017). At Light Speed: Advances in Optogenetic Systems for Regulating Cell Signaling Behavior. In Annual Review of Chemical Biomolecular Engineering (Vol. 176). https://doi.org/10.1016/j.physbeh.2017.03.040