New view of cellular delivery trucks reveals unexpected hitch
University of Michigan researchers have uncovered an unexpected tactic that one class of proteins uses to ferry cargo to its cellular destination. Their findings offer a new understanding of a process that is fundamental to the survival of cells in organisms from yeast to humans.
For all cells to function, specialized subunits called organelles must be transported to specific locations within the cell to perform their jobs. This process is managed by a system of motor proteins that load the cargos, carry them along the cell’s highways, and then deliver them to the right destinations at the right time.
A new study from the lab of U-M cell biologist Lois Weisman, Ph.D., sheds light on precisely how cargo hitches to one type of these cellular delivery trucks, called class V myosin motors (or myosin-V). These motor proteins play an essential role in a wide range of biological processes and are known to contribute to conditions ranging from neurological disorders to a life-threatening diarrheal disease when they malfunction.
“And so there’s a lot of interest in how these myosin-Vs work,” says Weisman, a professor at the U-M Medical School and the Life Sciences Institute (LSI), where her lab is located.
Weisman’s lab studies cellular transport using the model organism Saccharomyces cerevisiae (baker’s yeast), which rely on these processes to reproduce and have a high degree of evolutionary overlap with more complex organisms. Previous studies from her lab have demonstrated how the motor proteins know where and when to release the cargo.
For this study, her group wanted to examine the other end of the journey: how the cargo loads in the first place. Collaborating with structural biologist Michael Cianfrocco, Ph.D., at the LSI, they determined that the connection between adapter proteins (essentially the hitch that connects cargo to the motors) and myosin-V is more complex than previously believed.
“The theory in the field, including in our lab, was that these adaptor proteins bound to myosin-V on one of two places where they clustered and competed with each other,” Weisman explains. “But what we found is that the adaptor protein wraps around the motor and binds to at least two places, in what we now term a handhold mechanism”
This new structural model of the binding mechanism offers important insights into how this crucial process is tightly regulated to support proper cell function.
Previous efforts to determine the structure of the adaptor protein bound to myosin-V were hindered by the sheer pliability of the adaptors, which made them difficult to stabilize. However, advanced microscopy of the molecules allowed the team to discover that the adaptor bound the motor in a handhold mechanism. By combining results from this type of advanced microscopy with the AI structure prediction system AlphaFold, they were able to achieve a more detailed view of this complex than previously possible.
Weisman believes this stronger attachment may have evolved to keep cargo secured when the motor proteins had to traverse challenging environments, such as squeezing through the narrow pathway of a budding yeast cell.
“This new structural model of the binding mechanism offers important insights into how this crucial process is tightly regulated to support proper cell function,” says Lily Hahn, Ph.D., a former graduate student in the Weisman and Cianfrocco labs, who led the study. “And we also discovered a striking similarity in how yeast and mammalian myosin-V motors bind to their cargoes.”
Top image: Illustrated representation of cargo adaptor proteins wrapped around myosin V motor proteins in a 'handhold' mechanism. Illustration by Rajani Arora, U-M Life Sciences Institute
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“Cargo adaptors use a handhold mechanism to engage with myosin V for organelle transport,” Journal of Cell Biology. DOI: 10.1083/jcb.202408006