How does touch come about?Tsinghua University cracks the unsolved mystery of the Nobel Prize achievements and appears in Nature

When you swipe your phone, shake someone’s hand, or step on a rock, have you ever thought about:

Exactly how our bodies feel relatedforceof?

More specifically, how are these physical stimuli translated into bioelectrical signals? This is actually a question that even Nobel Prize winners have not figured out.

However, it has now beenTsinghua Universitycracked! The results are published in the latest issue of Nature:

Let’s see together.

The unsolved mystery of the Nobel Prize: How to feel mechanical force?

In fact, about how humans perceive mechanical force, someone discovered the corresponding receptor protein in 2010:PIEZO (meaning “stress” in Greek).

The 2021 Nobel Prize in Physiology or Medicine was awarded to the discoverer: Ardem Patapoutian, a Lebanese-born American molecular biologist and neurologist.

But more than ten years have passed, and the world has not figured out what the protein is under stress.How to generate bioelectrical signals.

Since PIEZO is stimulated for such a long time:

The technical term is called a trimeric three-bladed propeller-like structure.

There is conjecture that the hole in the center is responsible for ion permeability, and the three outer blades are responsible for mechanical force perception. When the cell membrane tension changes, PIEZO can change from the closed state to the flat shape shown in the above figure, driving the opening of the pores in the middle, thereby converting the mechanical stimulation into cation flow.

Is it really?

Researchers from Tsinghua University conducted the study accordingly.

Generally speaking, cryo-EM is required to resolve the structure of biological macromolecules. The biggest problem comes: how to introduce invisible force in the state of frozen sample to obtain the two different states of PIEZO in the conjecture?

After unremitting thinking, Tsinghua University drew on the predecessors to recombine membrane proteins into liposomes (a thing with the same structure as the skin cell membrane) in two different ways. higher, the greater the curvature of the curve) difference to introduce membrane tension.

What do you mean?

The radius of curvature of PIEZO1 (one of the PIEZO family) itself is close to 10 nm, and in liposomes of the same size, there is no deformation, and it is circular.

When it is reconstituted into larger liposomes in an outside-in manner, the difference in the radius of curvature creates a force between the two, and the protein and membrane are deformed, and the protein is in the shape of a droplet collapsed (the first row of the figure below). ).

In the outside-out mode, the curvature radii of the PIEZO1 protein and the liposome are diametrically opposite, and the interaction force between the membrane and the protein becomes larger, and the PIEZO1 is in a flattened state (the second row of the above figure).

Eventually, the researchers got PIEZO1 on the membraneTwo structures of collapsed state and force flattened, which supports the above conjecture. That is to say, the PIEZO1 protein has reversible deformation, and generates bioelectric signals through the “one-piece” state when subjected to force.

▲ The left is the folded shape, the right is the unfolded shape

Going a step further, they revealed how PIEZO1 uses its nanoscale curvature to detect pico-scale forces (1pN=10^-12N), becoming a class of ultrasensitive mechanoreceptors with low energy consumption.

And this surprised the authorThe beauty of the intersection of life processes and physical principles!

simply put:

In the resting state, the protein is in equilibrium (bowl surface area is 628 nm2, projected area is 314 nm2); when membrane tension changes, the equilibrium is disrupted, and the membrane drives the PIEZO1 protein to flatten together.

When the blade is flattened, the yellow “cap” above will also rotate slowly, so that the drain valve in the upper half of the channel area is opened, and the ions enter the channel sideways from the gap under the “cap”.

At the end, you may wonder, what’s the use of studying it?

Of course it is very useful, PIEZO has a very wide range of physiological and pathological functions (in the cardiovascular system, cardiomyocytes, and bone formation and remodeling, etc.), and it is necessary to understand its various mechanisms to carry outrelated drug design.

about the author

The co-author of this paper is a doctoral student at Tsinghua University and University of Science and Technology of China.Yang Xuzhong, Lin Chao, Chen Xudong, Li Shouqing.

The corresponding authors are Professor Xiao Bailong from the School of Pharmacy and Researcher Li Xueming from the School of Life Sciences of Tsinghua University.

Xiao Bailong graduated from the Department of Biochemistry of Sun Yat-Sen University with a bachelor’s degree and a Ph.D. from the University of Calgary in Canada. He did postdoctoral research at the Scripps Research Institute for 5 years, helping to promote the discovery and research of the Nobel Prize achievement PIEZO.

He is now a tenured professor and doctoral supervisor of the School of Pharmacy, Tsinghua University, and a recipient of the National Science Fund for Distinguished Young Scholars.

Xueming Li graduated from the University of Science and Technology Beijing with a bachelor’s degree and a Ph.D. from the Institute of Physics, Chinese Academy of Sciences. He did four years of postdoctoral research at the University of California, San Francisco.

Now he is a tenured associate professor at the School of Life Sciences, Tsinghua University, a researcher at the Tsinghua-Peking University Life Science Joint Center, the Advanced Innovation Center for Structural Biology, and the Frontier Research Center for Biological Structures.

In recent years, the main research direction is to introduce deep learning and particle filtering and other technologies into the field of cryo-electron microscopy.

Xiao Bailong and Li Xueming have cooperated in the research of PIEZO protein for many years. Before this result, a number of results have been published.

▲ Picture source Tsinghua University School of Pharmacy WeChat public account

Paper address:

https://www.nature.com/articles/s41586-022-04574-8