25 November 2020
Slowing down a molecular motor
Published online 6 July 2020
Molecular crowding slows down cargo carried inside cells by teams of motor proteins.
Animal and plant cells depend on motor proteins to transport cellular cargo needed for driving processes, such as protein homeostasis, that are vital to cellular function. These molecular motors are specialized proteins that bind to cargo, vesicles and organelles, and ‘step’ along thin microtubules, which are much like a network of roads in a city. How one group of motor proteins called kinesins operate in live cells is still a subject of ongoing investigation.
Now, a team of researchers in the United States, United Arab Emirates and the United Kingdom has shown that cargo carried by teams of kinesin motors are slowed down by crowds of molecules, but cargo carried by single kinesin motors does not appear to be affected.
“We discovered that crowding makes motors succumb to force more readily and fall off the road,” says biophysicist George Shubeita of New York University Abu Dhabi. “When pulled by a team of motors, the cargo is set back every time a motor falls off the road, which slows the team down. This does not happen when only one motor moves the cargo.”
The team demonstrated that macromolecular crowding slows down lipid droplet transport both in fruitfly embryos and in petri dishes in the lab. They also performed experiments that ruled out the possibility that other factors, such as viscous drag or a lack of the energy-carrying molecule ATP, might be involved in the slowdown.
“We have unravelled the details of how these motors carry cargo through the crowded cell, using tools such as very precise laser tweezers, which enabled us to pull on single molecules to probe their function,” Shubeita says. Since defects in molecular motor function are known to occur in disease, the work is a step forward in understanding how motors work in their native cellular environment, which could help pinpoint what goes wrong when motors cease to function properly.
Ajay Gopinathan of the Center for Cellular and Biomolecular Machines, University of California Merced, who was not involved in the study, says: “This elegant study appears to resolve previously reported contradictions between clean in vitro [in petri dishes] and crowded in vivo [in live organisms] studies, and lends support to a suggested model of the underlying molecular mechanism. This could spur focused experimental and theoretical efforts to directly address these effects at the molecular scale."
Nettesheim, G. et al. Macromolecular crowding acts as a physical regulator of intracellular transport. Nat. Phys. https://doi.org/10.1038/s41567-020-0957-y (2020).