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Inching to the top
Among proteins, as among people, sometimes you just need a little help to get along. That’s what a team of researchers in the NIDCD Laboratory of Cell Structure and Dynamics has recently discovered about a protein called myosin IIIB (MYO3B). MYO3B plays a supporting role in the growth and maintenance of stereocilia, the bristly protrusions from sensory hair cells in the inner ear that turn vibrations into the electrical signals that the brain recognizes as sound. Their finding is of interest not only to scientists who study hearing, but to cell biologists who want to understand more about how different kinds of proteins move molecules efficiently from one part of a cell to another.
The study, published in the February 21, 2012 Current Biology, reveals a novel bit of cooperation between two proteins that allows one to get the other to where it needs to go. This new discovery is but one in a series of findings that have come out of the lab of Bechara Kachar, M.D., which is exploring how a tight-knit group of proteins work together to build, maintain, and regulate the precise height of stereocilia.
An earlier paper from Dr. Kachar’s lab had shown how the motor protein myosin IIIA (MYO3A) transports espin-1 (ESPN1), an actin-binding cargo protein, to the stereocilia tip. This solved the mystery of how the building blocks of the stereocilia actin core could travel up the filament to rebuild and refresh the strands, rather like a truck (the motor) bringing a pallet of bricks (the cargo) to the building site. Another mystery, however, was how mutations in MYO3A could be associated with late-onset hearing loss if the protein was so essential to stereocilia regulation. The scientists thought that another motor protein had to be compensating for the lack of MYO3A—at least for some period of time.
A likely suspect was MYO3B, which has an almost identical structure to MYO3A except that it lacks an actin-binding tail—a segment of the protein that grabs onto the actin in the stereocilia and allows MYO3A to move up the filament, rather like an inchworm creeping up a flower stem.
A number of experiments showed that MYO3B could get to the tips of stereocilia, but only if it was accompanied by the cargo protein ESPN1. When ESPN1 was removed, MYO3B would not travel. Looking closely at ESPN1, the researchers saw that it just so happened to have an actin-binding tail in its structure. Through more experiments, they were able to surmise that MYO3B was enlisting the actin-binding tail of ESPN1 to give it an assist, a bit like a driver with a flat tire who happens to pick up a hitchhiker with a spare. ESPN1 provides the missing bit of machinery that MYO3B needs to move.
“While previous studies have shown that cargo can regulate the activity of motor proteins, this is the first time that any researchers have been able to show an actin-binding cargo protein directly participating in the motility mechanism,” says Uri Manor, Ph.D., a fellow in the Kachar lab who is a co-leading author on this study. Since myosins are involved in a vast number of cellular functions and dysfunctions, this new discovery could open doors to treatments not just for late-onset deafness, but for other conditions caused by genetic mutations in which similarly structured proteins could be called upon to compensate for each other.