These ‘Movies’ of Proteins in Action are Revealing the Hidden Biology of Cells

Ewen Callaway in Nature: Since the 1950s, scientists have had a pretty good idea of how muscles work. The protein at the centre of the action is myosin, a molecular motor that ratchets itself along rope-like strands of actin proteins — grasping, pulling, releasing and grasping again — to make muscle cells contract.

The basics were first explained in a pair of landmark papers in Nature1,2, and they have been confirmed and elaborated on by detailed molecular maps of myosin and its partners. Researchers think that myosin generates force by cocking back the long lever-like arm that is attached to the motor portion of the protein.

The only hitch is that scientists had never seen this fleeting pre-stroke state — until now.

In a preprint published in January3, researchers used a cutting-edge structural biology technique to record this moment, which lasts just milliseconds in living cells.

“It’s one of the things in the textbook you sort of gloss over,” says Stephen Muench, a structural biologist at the University of Leeds, UK, who co-led the study. “These are experiments that people wanted to do 40 years ago, but they just never had the technology.”

That technology — called time-resolved cryo-electron microscopy (cryo-EM) — now has structural biologists thinking like cinematographers, turning still snapshots of life’s molecular machinery into motion pictures that reveal how it works.

Muench and his colleagues’ myosin movie isn’t feature-length; it consists of just two frames showing different stages of the molecular motion. Yet it confirmed a decades-old theory and settled debates over the order of the steps in myosin’s choreography. Other researchers are focusing their new-found director’s eye on understanding cell-signalling systems, including those underlying opioid overdoses, the gene-editing juggernaut CRISPR–Cas9 and other molecular machines that have been mostly studied with highly detailed, yet static structural maps.

Researchers have been able to capture images of individual myosin proteins as they pull on an actin filament during muscle contraction, confirming key details of the motion. First, myosin becomes cocked or primed, then it attaches to actin and its lever arm swings in a power stroke that slides the filament by about 34 nanometres.Credit: Sean McMillan

“The big picture is to move away, as much as possible, from this single, static snapshot,” says Georgios Skiniotis, a structural biologist at Stanford University in California, whose team used the technique to record the activation of a type of cell-signalling molecule called a G-protein-coupled receptor (GPCR)4. “I want the movie.”

More here.