Bengaluru scientists help find new kind of molecular motor

Scientists have found a previously unknown kind of molecular machine involved in important cellular processes.

Updated - May 05, 2023 08:25 am IST

Published - May 04, 2023 08:30 pm IST - Chennai

Anupam Singh, a researcher at NCBS, uses an instrument as part of the study.

Anupam Singh, a researcher at NCBS, uses an instrument as part of the study. | Photo Credit: Anupam Singh/Special arrangement

An international team of researchers, including from the National Centre for Biological Sciences (NCBS), Bengaluru, has reported a new kind of molecular motor. The finding, significant in its own right, also opens the door to previously unanticipated cellular processes and potential applications in biology and medicine.

Their paper was published in Nature Physics on May 4.

What is a molecular motor?

Each cell in the body is a complex soup of electrochemical reactions that produce energy, but they’re not enough. Cells also need to move things, such as pull two organelles together, move cargo towards and away from the nucleus, and power the movement of molecules inside cells.

Many of these actions are driven by molecular motors, which use biochemical energy to do mechanical work.

“Disruption or deregulation in these processes can lead to deleterious effects which can manifest as different diseases,” Saikat Chowdhury, a senior scientist at the CSIR-Centre for Cellular and Molecular Biology, Hyderabad, said in an email. He wasn’t involved in the new study.

In a 2016 paper, researchers from Australia and Germany reported that when an enzyme called Rab5 binds to a long protein called EEA1, the protein loses its taut and rigid shape and becomes floppy. This ‘collapse’ pulls two membranes inside a cell closer to each other.

What has the new study found?

In the new study, researchers have reported that EEA1 regains its rigid shape in another mechanism so that it can become floppy again to pull the membranes closer, creating a new kind of two-part molecular motor.

At the time the 2016 paper was published, it was unclear whether EEA1 could resume its rigid shape, so that the whole process could repeat itself without the help of other proteins.

The researchers reasoned that it had to resume its stiffer shape because EEA1 works on thousands of membranes, and creating a molecule as big as the protein for every membrane pair would be wasteful.

At more than 200 nm, EEA is more than 100x longer than typical proteins.

“A long standing question in the field is how EEA1-like molecules go back to their elongated conformation”; the new study addresses this question for the first time, Dr. Chowdhury said.

The NCBS & co. group reported that EEA1 draws energy from a reaction called GTP hydrolysis to become rigid again. GTP hydrolysis is mediated by enzymes called GTPases. Rab5 is one such.

“Due to the ubiquitous pairing of small GTPases with such long molecules in eukaryotic cells, we believe this will mark a new class of molecular machines that operate as motors in a unique way and with novel collective effects,” Shashi Thutupalli, a coauthor of the study, said in an email.

Dr. Thutupalli is with the Simons Centre for the Study of Living Machines, NCBS. His collaborators are with the Max Planck Institute of Molecular Cell Biology and Genetics and the Cluster of Excellence Physics of Life, TU Dresden (both in Germany).

Why is the finding significant?

They have reported several novelties in their findings. The motor doesn’t produce a lever-like back-and-forth action, as most motors do, but allows a molecule to change its flexibility between two states. Also, most molecular motors get their energy from another molecule called ATP, whereas the Rab5-EEA1 motor uses GTP.

“Almost all the other motors that we know ‘walk’: they go one way,” Dr. Thutupalli said, whereas “this motor … collapses and extends again, in the same place.”

EEA1 can have one of several trillion shapes when it is floppy, but it can have only one (rod-like) shape when it is stiff. The floppy state has more entropy and is thus “entropically favoured”, per Dr. Thutupalli. So when it goes from stiff to floppy, it exerts an entropic force on the membranes that it pulls.

“No other motor uses this force.”

What are the potential applications?

Finding out how a single molecule moves inside a cell is difficult, but Dr. Thutupalli said two students, Anupam Singh and Joan Antoni Soler, found a “clever” way. Instead of trying to study the whole protein, they attached a small fluorescent molecule to one end of EEA1, “like a fly atop the Qutub Minar”.

Then they used fluorescence correlation spectroscopy to track how the fluorescent molecule moved as Rab5 and EEA1 interacted.

They combined these observations with a concept in mechanics that lets engineers calculate the stiffness of an object by observing just one end.

“This study is not only relevant for understanding membrane fusion by EEA1 but also provides a general mechanism which is applicable for many such mechanochemical proteins or assemblies, which harness chemical energy of nucleotide hydrolysis for mechanical work in the cell,” Dr. Chowdhury said.

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