Susanna Liu

A team of Yale and University of Pennsylvania researchers recently discovered that myosin, one of the proteins responsible for muscle contraction, can sense and adapt to different amounts of force.

The study, published on Jan. 22 in the Proceedings of the National Academy of Sciences, used cryo-EM — a new technology that allows researchers to determine the structures of complex biological molecules — to visualize actin and myosin binding at a high resolution. Led by Yale professor Charles Sindelar and Penn professor Michael Ostap, the collaboration is the first of its kind to reveal that myosin can sense and respond to different forces.

“Myosins do this really amazing thing: They convert chemical energy into mechanical work,” Ostap said. “In our study, we discovered that myosins are able to sense different mechanical stimuli and respond accordingly.”

Muscles are composed of two repeating protein filaments: myosin and actin. Muscle contraction occurs when myosin, which acts as a cell motor, pulls along chains of actin. The synchronized movement of many myosin and actin filaments allows for hands to grasp a mug or for eyes to gaze over a text. But, as Ostap explained, myosin is versatile and found in nearly every cell of the body. His and Sindelar’s research targeted the myosin found throughout the body, not only the myosin in muscle cells.

Andrew Huehn GRD ’20 was in charge of preparing and analyzing the myosin samples. He explained that myosin is involved in a whole host of cellular processes, from muscle contraction to organelle movement.

Although Ostap’s lab specializes in myosin mechanics and biochemistry, only recently was the lab able to see myosin in action.

Yale biophysicist Yong Xiong explained that a couple of years ago, the Ostap lab would have needed to use X-ray crystallography, a technique used to determine the structure of crystallized proteins by studying how the proteins diffract X-rays.

“In order to use X-ray crystallography, we must count on the ability of proteins to form highly ordered crystals,” Xiong said. “Sometimes, proteins cannot do this.”

Cryo-EM, a promising new technology, uses electrons instead of X-ray beams to visualize proteins. As a result, cryo-EM allows researchers to determine the structures of molecules that could not be seen using X-ray crystallography.

“In this study, the myosin proteins were bound to filaments, and you can’t crystallize the filaments that have the proteins bound to them,” Ostap explained. “Therefore, cryo-EM was very helpful. The Sindelar Lab at Yale is an expert in cryo-EM, and our collaboration with them made it finally possible to visualize myosin structure and function.”

Ostap said that researchers must develop a better understanding of the basic biochemistry and mechanics of these motors before they can recognize the motors’ molecular roles.

“We now understand that myosin can respond to different forces, but how do we tune that?” Ostap said. “How do we make one myosin very force sensitive, while we make another myosin less force sensitive? What are the differences in the proteins that allow these different force sensitivities to occur?”

While the focus of the paper was on actin and myosin, the Yale-Penn collaboration also cracked the structure of phalloidin, an important drug that is used to stabilize actin filaments. Although Ostap said the discovery was “kind of a side thing in the paper,” he noted that those studying actin will find it equally important.

The cryo-EM microscope at Yale cost $8 million and will be moved to the new science building upon its completion.

Lorenzo Arvanitis |