A nano torch for cells

Researchers at the Institute for Stem Cell Science and Regenerative Medicine (inStem), Bengaluru, have developed a molecular sensor that can identify cancer drugs by detecting how such chemicals modify the microtubules inside living cells.

Microtubules are part of the cytoskeleton, a structural network within the cell’s cytoplasm, and they alter in response to several chemicals. This protein filament network extends throughout the cell, gives the cell shape, keeps its organelles in place. It also has a role in cell movement, cell division and transporting materials within cells.

“An important function of microtubule in cells is that it helps divide the genome (DNA) correctly when a cell divides,” says Minhaj Sirajuddin, assistant investigator, inStem. “So, drugs that target microtubules have been exploited in treating cancer, such as taxol and vincristine,” Sirajuddin told Quantum .

Cytoskeletal assemblies such as actin and microtubules provide the framework for maintaining cell integrity and power biological motions. A few examples of biological motions include heart and muscle contraction, sperm motility and intracellular transport of cargos in metre-long neurons. Due to their important functions in cell physiology, mutations in cytoskeletal components have been linked to a variety of human diseases such as cardiomyopathy, muscular dystrophy and neurodegenerative diseases.

Understanding tubulin modifications has remained a challenge till date because of the unavailability of tools that can mark them in living cells. Researchers from inStem, in collaboration with Curie Institute, Orsay, France, have solved this by developing a tubulin nano-sensor, the first of its kind, to study the dynamics of microtubule modifications in living cells and use this for identification of new cancer therapeutic drugs.

Researchers typically have limited options to look at the microtubules without affecting their function. Sirajuddin’s team identified a molecule that can “illuminate” microtubules in cells using a microscope. “The molecule we identified does not affect microtubule properties — this is the underlying difference from the current range of molecules that illuminate microtubules,” he says.

The researchers made synthetic proteins known as nanobodies, which can bind specifically to modified microtubules. These nanobodies are similar to the antibodies made in our body as a defence against pathogens. However, the nanobodies are smaller and amenable for protein engineering. The nanobody was coupled with a fluorescent molecule to serve as a ‘sensor’. The research team developed and validated a live cell sensor against a unique microtubule modification called ‘tyrosinated form’, known to be important for cell division and intracellular organisation.

The tyrosination sensor is the first tubulin nanobody that can be used to study the dynamics of microtubule modifications in living cells. CEFIPRA researchers have shown the application of this sensor in studying the effect of small-molecule compounds that target microtubules. These chemicals are frequently used as anti-cancer drugs. Thus, the tyrosination sensor will facilitate studying microtubule functions for many researchers and will aid in identifying new drugs of therapeutic value.

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