Scientists discover the basics of how piezoelectric proteins are sensitive to pressure

A team of scientists from Weill Cornell Medicine and Rockefeller University has shed light on the basic mechanism of piezoelectric proteins, which serve as sensors to the body for mechanical stimuli such as touch, bladder and pressure blood. This discovery is a feat of basic science that also opens up many new avenues for investigation of the role of piezo proteins in human diseases and potential new therapeutic strategies.

In the study, published August 21 in Nature, scientists have used advanced microscopy techniques to image Piezo1 protein at rest and during the application of mechanical forces. They confirmed the structure of this complex protein and essentially showed how it can convert mechanical stimuli into an electrical signal.

"Our analysis shows that the tension on the cell membrane in which Piezo1 is integrated can flatten and expand the structure of the protein," said senior co-author Dr. Simon Scheuring, professor of physiology and biophysics in Weill anesthesiology. Cornell Medicine. Dr. Scheuring and his lab collaborated in the study with the laboratory of Dr. Roderick MacKinnon, Professor of Molecular Neurobiology and Biophysics at Rockefeller University. Dr. MacKinnon was co-recipient of the 2003 Nobel Prize in Chemistry for his work on the determination of ion channel protein structures and mechanisms.

Piezo1 and Piezo2 are very large and complex proteins with unique structures. They are integrated in the membranes of certain types of cells and have the function of converting the mechanical force exerted on the cells into electrical signals modifying the cellular activity. Piezo proteins, for example, act in bladder cells to detect when the bladder is full and in the cells lining the blood vessels to detect and help regulate changes in blood pressure. Piezo2 proteins act on the sensory nerve endings of the skin and joints, helping to mediate the senses of touch, pain and proprioception – the sense of limb disposition.

Advances in imaging techniques have allowed scientists in recent years to determine the basic structure of Piezo1, a structure that Piezo2 is supposed to share primarily. From above, this structure has a three-armed, propeller or "triskelion" appearance.

On the side, it looks like a shallow bowl embedded in the cell membrane, with an ion channel at its center. The latter, when open, allows a flow of calcium and other positively charged ions into the cell.

The basic mechanism by which the mechanical force opens the ion channel has remained mysterious. But in the new study, Dr. Scheuring and Dr. MacKinnon and their colleagues, including the lead author, Dr. Yi-Chih Lin, postdoctoral associate in Anesthesiology, were able to get a clearer picture of how this works.

They combined cryo-electron microscopy with a lesser known technique called high-speed atomic force microscopy, which produces an image of an object essentially by palpating its surface with the help of a mechanical probe. super sensitive. They showed with these methods that Piezo1 is an elastic structure that normally bends the cell membrane where it rests, but flattens out when a mechanical force is applied to the cell membrane, for example.

"As the membrane tension increases, the structure of the Piezo1 flattens and expands to occupy a larger area, which in turn opens the ion channel," said Dr. Scheuring.

He evoked the possibility that other stimuli stretching and flattening the piezoelectric structure, such as a pulling force exerted on his arms from the inside or on an external domain called CED from the outside. outside the cell, could in principle open the ion channel. a versatile mechanism adapted to the wide range of cell types and physiological functions in which it operates.

In addition, given this wide range of cell types – in organs such as the lungs, bladder, intestines and pancreas, as well as in the blood vessels and the sensory nervous system – the discovery of the basic mechanism of the Piezoprotein protein could understand and treat many human diseases. To take one example, Dr. Scheuring said that if the membranes of the cells lining the blood vessels contain excess cholesterol, they would become stiffer, which would increase the background voltage of the integrated Piezo 1 proteins and potentially disrupt the ability normal of these proteins to detect and regulate blood pressure. .

"Our discovery leads to many predictions about the role of piezo proteins in the disease, which we and others can now study and study," he said.