Tiny molecular motors shed light on cell function, say Stanford researchers

STANFORD, Calif. – Every cell in the body has what James Spudich, PhD, calls 'a dynamic city plan' comprised of molecular highways, construction crews, street signs, cars, fuel and exhaust. Maintenance of this highly organized structure is fundamental to the development and function of all cells, Spudich says, and much of it can be understood by figuring out how the molecular motors do the work to keep cells orderly.

Spudich, biochemistry professor at the Stanford University School of Medicine, and Stanford physics graduate student David M. Altman report in the March 5 issue of Cell how a type of molecular motor provides the rigidity needed by the tiny sensors in the inner ear in order to respond to sound. They found that this motor creates the proper amount of tension in the sensors and anchors itself to maintain that tension.

'Our general feeling is that tension-sensitive machines are at the heart of the dynamic city plan,' said Spudich. Their National Institutes of Health-funded study has implications far beyond how an obscure molecule provides rigidity for a protein in the inner ear. A motor able to create structural changes by taking up slack in proteins and clamping down so that they remain in a rigid position may help explain many intricacies of cellular organization, such as how chromosomes line up and separate during cell division.

'Studies like this allow you to understand enough details of these motors to design small molecules to affect their function,' said Spudich, who is also the Douglass M. and Nola Leishman Professor of Cardiovascular Disease. Toward this end he has co-founded a company, Cytokinetics, in hopes of creating drugs that selectively target molecular motors involved in cancer and cardiovascular disease.

For years, Spudich's lab has studied molecular motors called myosins, proteins that carry out cellular motion by attaching to and 'walking' along fibers of actin. The interaction of actin and myosin is the mechanism behind cell actions such as muscle contractions, the pinching off of two daughter cells from a mother cell during division and the hauling of cargo molecules around in a cell. Of the 18 types of myosin molecules, their current findings examine myosin VI, thought to be responsible for setting the tension for stereocilia, actin-filled rods on the sound-sensing hair cells of the inner ear. A defect in myosin VI results in deafness.

Although it was known that myosin moves along actin fibers, it had never previously been demonstrated how myosin could function as an anchor or a clamp. To study this, Spudich and Altman needed techniques beyond the realm of biology. 'This is a problem for physicists who think in terms of forces and putting a load on a system,' said Spudich. Altman specializes in optical tweezers, a focused laser that allows the manipulation of microscopic beads, and provided the required physics know-how by applying his expertise to studying myosin activity precisely.

The Cell paper includes a number of complex equations describing how the myosin VI anchor works, but the researchers have easily simplified the concept: think of the palm of an open hand as the hair cell and the fingers as the stereocilia. Myosin VI has two legs as well as a tail, which can bind to other things. The researchers think the myosin VI tail in the hair cell binds to the webbing between the fingers - the cell membrane between the stereocilia - and then as the legs walk across the palm (the hair cell) it pulls the webbing between the fingers taut which makes the stereocilia rigid.

As the motor continues walking, the taut membrane strains the motor and distorts its shape, which turns the motor into an anchor. If the webbing/membrane becomes slack again, the motor regains its normal shape and begins walking again. It continues walking until the membrane becomes taut again.

'You can imagine that if a motor like this didn't stall, it would end up continuing to burn energy in the cell and would keep pulling this membrane, but it would be wasting a lot of energy,' said Altman, who is first author of the paper. 'So this change has made it a smart and efficient motor.'

'The sophistication of what David has been able to do here in terms of looking at a single molecule and how it behaves is unusual,' Spudich noted. 'There are very few proteins in biology that have been analyzed and understood down to this level.' Altman is now looking at defective myosin VI that causes deafness in hopes of learning even more about the precise refinement of the molecular motor.