The ability to sense mechanical stimuli, like touch or blood pressure, is essential to physiological processes in humans and across the animal kingdom. In a new study, Scripps Research scientists show how the sensory ion channel PIEZO1 changes shape in response to mechanical stimuli, revealing critical information about how this protein functions.
, in contrast to the contracted, cup-like conformation predicted by previous cell-free structural models. This structural finding could lead to future drug discovery applications, like screening for effective medicines related to diseases associated with congenital PIEZO1 defects, such as autosomal recessive congenital lymphatic dysplasia and hereditary xerocytosis.
PIEZO1 is shaped like a three-bladed propeller, and its blades are thought to be the primary sensors of mechanical force, so understanding their structure is critical to understanding how the sensor functions. However, prior models that were based onlacked information on how the tips of these blades are structured.
The researchers labeled PIEZO1 with fluorescent markers and used the microscopes to image the protein in different situations: at rest, when exposed to a chemical inhibitor, and when activated via stretching of the cell membrane. Scripps Research scientists used super-high resolution fluorescent microscopy to sample molecular positions , ultimately revealing the protein's shape at the nanometer-scale. Credit: Eric Mulhall, Scripps Research.
The team's single-molecule analysis also revealed that PIEZO1's blades are relatively rigid at their base but more flexible at their ends, which has implications for how sensitive the sensors are to."Having the blades be floppy at their ends might help dampen the background mechanical noise inside a cell," says Mulhall.
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