A new biosensor designed by Penn State researchers is giving scientists the first dynamic glimpses of manganese, an elusive metal ion essential to life.
The researchers designed the sensor from a natural protein called lanmodulin, which binds rare earth elements with high selectivity, and was discovered 5 years ago by some Penn State researchers involved in the current study.
They were able to genetically reprogram the protein to prefer manganese over other common transition metals such as iron and copper, which defies trends observed with most transition metal binding molecules.
The sensor could have wide applications in biotechnology to advance understanding of photosynthesis, host-pathogen interactions and neuroscience. It can also be generally applied to processes such as separation of transition metal components (manganese, cobalt and nickel) in the recycling of lithium-ion batteries.
The team recently published their findings in Proceedings of the National Academy of Sciences.
“We believe this is the first sensor selective enough for manganese to conduct detailed studies of this metal in biological systems,” said Jennifer Park, a Penn State graduate student and lead author of the paper. “We used it — and we saw the dynamics of how manganese gets into and is present in a living system, which wasn’t possible before.”
She explained that the team was able to monitor manganese behavior inside bacteria and is now engineering more tight-binding sensors to study how the mineral works in mammalian systems.
Manganese is an essential mineral for plants and animals, as is iron, copper, and zinc. Its function is to activate enzymes – molecules with vital functions within living systems. For example, manganese is a key component of photosynthesis in plants – manganese is found at the site where water is converted to oxygen at the heart of photosynthesis. In humans, manganese is linked to neurological development. The researchers explained that excess manganese buildup in the brain leads to a motor disease similar to Parkinson’s, while low levels of manganese have been observed with Huntington’s disease.
However, scientific understanding of manganese has lagged behind that of other essential minerals, in part due to a lack of techniques to visualize its concentration, localization, and movement within cells. The new sensor opens the door to all kinds of new research, explains Joseph Cutrovo, assistant professor of chemistry at Penn State and senior author of the paper.
“There are a lot of potential applications for this sensor,” Cutrovo said. “I personally am particularly interested in seeing how manganese interacts with pathogens.”
He explained that the body works hard to reduce the iron that most bacterial pathogens need to survive, so these pathogens instead turn to manganese.
“We know there’s a tug-of-war of vital minerals between the immune system and invading pathogens, but we haven’t been able to fully understand these dynamics, because we haven’t been able to see it in real time,” he said. , adding that with the new capabilities to visualize the process, researchers have tools to develop novel drug targets for a range of infections that have emerged resistant to common antibiotics, such as Staphylococcus aureus (MRSA).
Cutrovo explained that designing proteins to bind to specific metals is a challenging intrinsic problem, because there are so many similarities between transition metals found in cells. As a result, there has been a lack of chemical biology tools to study the physiology of manganese in living cells.
“The question for us was, can we engineer a protein to bind to just one thing, a manganese ion, even in the presence of a large excess of other very similar things, such as calcium, magnesium, iron, and zinc ions?” Cutrovo said. “What we had to do was create a binding site arranged in just the right way, so that this protein bond is more stable in manganese than in any other metal.”
Having successfully demonstrated that lanmodulin is capable of such a task, the team now plans to use it as a scaffold with which to develop other types of biological tools to sense and recover many different metal ions that are of biological and technological interest.
“If you can figure out ways to differentiate minerals that are very similar, that’s really powerful,” Cutrovo said. “If we can take lanmodulin and convert it into a manganese-binding protein, what else can we do?”
Other co-authors on the paper are Joseph Mattox and Jiansong Xu from Penn State; Michael Cleary, Huan Wang, and Eric Gill of Massachusetts General Hospital and Harvard Medical School; and Danyang Lee and Somshovra Mukhopadhyay of the University of Texas at Austin.
The National Institutes of Health and start-up funding from Penn State supported this work.