How does the sense of touch come about? Tsinghua University solves the mystery of the Nobel Prize-winning work, published in Nature

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When you are browsing your phone, shaking hands with others, or stepping on a stone, have you ever thought:

How exactly does our body sense the relevant forces ?

More specifically, how are these physical stimuli converted into bioelectric signals?

This is actually a question that even Nobel Prize winners have not figured out.

However, it has now been cracked by Tsinghua University ! The results were published in the latest issue of Nature:

Let’s watch it together.

Unsolved Nobel Prize Mystery: How to Sense Mechanical Force?

In fact, regarding how humans perceive mechanical force, someone discovered the corresponding receptor protein in 2010: PIEZO (which means "pressure" 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.

However, more than a decade has passed, and the world still has not figured out how this protein generates bioelectric signals when subjected to force .

Because PIEZO is stimulated, it looks like this:

The professional term is trimer three-blade propeller structure.

It is speculated that the central channel 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 a closed state to a flat state as shown in the above picture, driving the middle channel to open, thereby converting mechanical force stimulation into cation flow.

Is it really?

Researchers from Tsinghua University conducted research based on this.

Generally speaking, cryo-electron microscopy is required to resolve the structure of biological macromolecules.

The biggest challenge now arises: How to introduce invisible forces into the frozen sample state to obtain the two different states of PIEZO as hypothesized?

After unremitting thinking, Tsinghua University learned from predecessors and reorganized membrane proteins into liposomes (a thing with the same structure as skin cell membranes) in two different ways , introducing membrane tension through the difference in curvature between proteins and liposomes (the higher the value, the greater the curvature of the curve) .

What does it mean?

The curvature radius of PIEZO1 (a member of the PIEZO family) itself is close to 10nm. When it is in liposomes of the same size, it does not deform and is round.

When it is reorganized into a larger liposome in an outside-in manner, the difference in curvature radius generates a force between the two, causing the protein and the membrane to deform, and the protein now takes on the shape of a collapsed water droplet (first row in the figure below) .

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

Finally, the researchers obtained two structures of PIEZO1 on the membrane: a folded state and a flattened state under force , which confirmed the above hypothesis .

That is, the PIEZO1 protein has reversible deformation, and generates bioelectric signals through a "opening and closing" state when subjected to force .

△ The left is folded, the right is expanded

Going a step further, they revealed how PIEZO1 uses its nanoscale curvature deformation to detect piconewton-scale forces (1pN=10-12N ⁾ , becoming a type of low-energy, ultra-sensitive mechanical force receptor.

This made the author marvel at the 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 628nm2, projected area is 314nm2) ; when the membrane tension changes, the balance is broken, and the membrane drives the PIEZO1 protein to flatten together.

When the blades are flattened, the yellow "hat" above will also rotate slowly , causing the drain valve in the upper half of the channel area to open, and the ions will enter the channel laterally from the gap under the "hat".

After reading to the end, you may wonder, what is the point of studying it?

Of course it is useful. PIEZO has a wide range of physiological and pathological functions (in the cardiovascular system, myocardial cells, and bone formation and remodeling) . Only by clarifying its various mechanisms can we design relevant drugs.

about the author

The co-authors of this paper are doctoral students Yang Xuzhong, Lin Chao, Chen Xudong and Li Shouqing from Tsinghua University and USTC.

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

Xiao Bailong graduated from the Department of Biochemistry of Sun Yat-sen University with a bachelor's degree and received his doctorate from the University of Calgary in Canada. He did postdoctoral research at the Scripps Research Institute in the United States for 5 years, helping to promote the discovery and research of the Nobel Prize-winning achievement PIEZO .

He is currently a tenured professor and doctoral supervisor at the School of Pharmacy of Tsinghua University, and a recipient of the National Outstanding Young Scientist Fund.

Li Xueming received his bachelor's and master's degrees from the University of Science and Technology Beijing, and his doctorate from the Institute of Physics, Chinese Academy of Sciences. He did four years of postdoctoral research at the University of California, San Francisco.

He is currently a tenured associate professor at the School of Life Sciences of Tsinghua University, and a researcher at the Tsinghua-Peking University Joint Center for Life Sciences, the Advanced Innovation Center for Structural Biology, and the Frontier Research Center for Biostructure.

His research direction in recent years has mainly been to introduce multiple technologies such as deep learning and particle filtering into the field of cryo-electron microscopy.

Xiao Bailong and Li Xueming have been collaborating on the study of PIEZO protein for many years and have published many results before this one.

△ Photo source: Tsinghua University School of Pharmacy WeChat official account

For more details about this study, interested readers are welcome to check out the original article.

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

Reference link:
https://mp.weixin.qq.com/s/pI_sLUv6IVnvwafakX61wQ