Fluorescent biosensor shines light on the activity of the rare-earth metal manganese

Written by Jack Lodge - Bioanalysis
Biosensors News

An innovative biosensor, designed by researchers from Penn State University (PA, USA), has provided scientists with the first ever dynamic views of the elusive metal ion, manganese.

Manganese plays an essential role in macronutrient metabolism, bone formation and free radical defense systems. Selective recognition of manganese has previously proven to be of high difficulty, as it is a first-row transition metal ion, which is known to bind with the lowest affinity to ligands.

In the past, the design of selective metal-binding sites remained challenging in both small-molecule and macromolecular chemistry. However, the research team created this new biosensor from a protein called lanmodulin. Lanmodulin binds rare earth elements that have high selectivity and was discovered 5 years ago by the very same researchers from Penn State University involved in the present study.

The researchers were able to genetically reprogram the Lanmodulin to prefer manganese over other familiar metals such as copper and iron. The sensor is thought to have wide-ranging applications in biotechnology that could enhance our knowledge of photosynthesis, host-pathogen interactions, and neurobiology. The research team has published their new findings in the journal, Proceedings of the National Academy of Sciences.

“We believe that this is the first sensor that is selective enough for manganese for detailed studies of this metal in biological systems,” said Jennifer Park, a graduate student at Penn State and lead author of the paper. “We’ve used it — and seen the dynamics of how manganese comes and goes in a living system, which hasn’t been possible before.”

The behavior of manganese was also monitored within bacteria and the research team is currently working to manufacture binding sensors that can possibly reveal how the metal works in mammalian systems. Manganese is an essential metal for both plants and animals, with its function being to activate enzymes within living systems. For example in plants, manganese is present at the site where water is converted to oxygen, and in humans, manganese is supplied to the brain and is associated with neural growth.

The new biosensor has broadened the avenues for all kinds of new research. In the past, scientific understanding of manganese fell behind that of other essential metals, partly due to the absence of methods to observe its levels, position, and mobility within cells.

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“There are so many potential applications for this sensor,” explained Joseph Cotruvo, associate professor of chemistry at Penn State and senior author of the paper. “Personally, I am particularly interested in seeing how manganese interacts with pathogens.”

Due to the fact that the human body works to restrict the amount of iron available to bacterial pathogens, which are essential for their survival, these pathogens look to manganese as a replacement.

Joseph further commented,

“We know there is this tug-of-war for vital metals between the immune system and these invading pathogens, but we haven’t been able to fully understand these dynamics, because we couldn’t see them in real time,” adding that with new capabilities to visualize the process, researchers have tools to potentially develop new drug targets for a range of infections for which resistance has emerged to common antibiotics, like staph (MRSA).

Developing proteins that can selectively bind to specific metals are inherently challenging, due to the many similarities between the transition metals present in cells. This has resulted in a shortage of chemical biology tools available to investigate the physiology of manganese in living cells.

“The question for us was, can we engineer a protein to only bind to one thing, a manganese ion, even in the presence of a huge excess of other very similar-looking things, like calcium, magnesium, iron, and zinc ions?” Cotruvo said. “What we had to do was create a binding site arranged in just the right way, so that this protein bond was more stable in manganese than any other metal.”

After successfully showcasing lanmodulin’s capability, the team is now intending to utilize it as a framework for the development of other biological instruments that can sense and retrieve various metal ions that hold biological and technological significance.

Cotruvo finally stated,

“If you can figure out ways of discriminating between very similar metals, that’s really powerful […] If we can take lanmodulin and turn it into a manganese-binding protein, then what else can we do?”

Source: Park J, Cleary M, Cotruvo Jr. J, et al. A genetically encoded fluorescent sensor for manganese (II), engineered from lanmodulin. PNAS. 119 (51) e2212723119 (2022), https://www.eurekalert.org/news-releases/982271