Newest variant of mScarlet3 to help track protein movements in living cells

Biologists frequently utilize a method to figure out why a cell divides, secretes hormones, or sends a signal to another cell. They attach colored lights to the proteins of interest so that they can see their motions and interactions in living cells under a microscope. The more colors these lights have, the more processes they can carry out at the same time.

Cell Division

Image Credit: Nixx Photography/

The first time a fluorescent protein was utilized as a colored marker in a cell was in the 1990s. The green protein originated from a fluorescent jellyfish. Changes were made to that green protein, resulting in blue, turquoise, and yellow variations.

A red fluorescent protein was found in corals in the 2000s. It was harder to convert this protein into a useful and strong red light for cell research.

Creation mScarlet3

A new bright red fluorescent protein that represented a significant advancement was successfully created in 2016 by the research group led by University of Amsterdam biologist Dorus Gadella. That protein was given the moniker mScarlet.

The scientific community instantly recognized their red bright protein. Nearly every country in the world currently uses the DNA encoding mScarlet for cell biology research after it was requested 3,400 times.

Unfortunately, the mScarlet protein turned out to fold more slowly and insufficiently in mammalian cells than the often-utilized green fluorescent proteins, resulting in less ideal brightness in these cells. To speed up and maximize the folding, the scientists kept working on the protein.

They applied two mScarlet variations they had already created: one with quick folding but reduced brightness, and one with slow folding but eventually bright fluorescence. They attempted to create a new protein by fusing the beneficial features of these two.

They were able to do this by making a series of precise adjustments to the protein's structure, which gave rise to mScarlet3. The most recent version now combines maximum brightness with quick and efficient folding.

Finally, the biologists sent mScarlet3 to the Institut de Biologie Structurale in Grenoble (CNRS, CEA, Université Grenoble Alpes) to test its structure. The world’s brightest X-Ray source, the European Synchrotron ESRF, was employed by structural biologist Antoine Royant to map the protein's molecular structure.

It turned out that mScarlet3 is so bright because of a special hydrophobic (oily) local structure in the protein, which both speeds up and improves the folding of the protein.

Antoine Royant, Structural Biologist, European Synchrotron ESRF

New standard

The toolbox that scientists have at their disposal in the lab is now more comprehensive than ever, thanks to this new, significantly enhanced version of the red fluorescent protein.

The experiences with mScarlet were already very positive, which is why we expect that mScarlet3 will become even more popular among researchers and will quickly become the new standard worldwide. Bright red fluorescent proteins are highly sought after because excitation of these red proteins is less harmful to cells than exciting green proteins.”

Dorus Gadella, Biologist, University of Amsterdam

Gadella added, “In addition, red light is scattered less, which means that you can also use the microscope to look at molecular processes in deeper cell layers. With mScarlet3 we finally have a very robust bright red fluorescent protein that folds quickly and completely without further disadvantages. We expect a lot from new applications with mScarlet3, including for making new red fluorescent biosensors where mScarlet3 can be used to image specific cell functions.

The UvA owns a patent on the mScarlet3 genetic code.

Journal reference:

Gadella, T. W. J., et al. (2023). mScarlet3: a brilliant and fast-maturing red fluorescent protein. Nature Methods.


The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of AZoLifeSciences.
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