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When you swipe your phone, shake hands with someone, or step on a rock, have you ever thought:
How exactly does our body feel the associated force?
More specifically, how are these physical stimuli converted into bioelectrical signals?
This is actually a problem that even Nobel laureates have not figured out.
However, now it has been cracked by Tsinghua University! The results are published in the latest issue of Nature:
Let's take a look.
The Unsolved Mystery of the Nobel Prize: How to Feel the Mechanical Force?
In fact, regarding how humans perceive mechanical forces, in 2010, someone discovered the corresponding receptor protein: PIEZO (Greek for "pressure").
The 2021 Nobel Prize in Physiology or Medicine went to the discoverer: Ardem Patapoutian, a Lebanese-born American molecular biologist and neuroscientist.
But more than a decade later, the world has not figured out how the protein produces bioelectric signals when stressed.
Since PIEZO is stimulated for this length:
The technical term is called a trimer trilobe propeller-like structure.
It has been speculated that the aperture in its center is responsible for ion permeability, and the outer three blades are responsible for mechanical force perception.
When the cell membrane tension changes, PIEZO can change from a closed state to a flattened shape in the figure above, driving the opening of the middle pore channel, thereby converting mechanical force stimulation into cation flow.
Is this really the case?
Researchers at Tsinghua University have conducted research based on this.
In general, cryo-EM is required to resolve the structure of biological macromolecules.
The biggest problem arises: how to introduce invisible forces in the frozen sample state and obtain the two different states of the conjecture PIEZO?
After unremitting thinking, Tsinghua University borrowed from its predecessors to recombine membrane proteins in two different ways into liposomes (something with the same structure as the membrane of skin cells), and introduced membrane tension through the difference in curvature between the protein and the liposomes (the higher the value, the greater the degree of curvature of the curve).
What does it mean?
PIEZO1 (one of the PIEZO family) itself has a radius of curvature of nearly 10 nm, and when it is in a liposome of the same size, it will not be deformed and will be round.
When it is recombined into a larger liposome in the form of an outlook-in, the difference in radius of curvature creates a force between the two, and the protein and membrane are deformed, at which point the protein is water droplet-convergent (line 1 below).
In the outside-out mode, the radius of curvature of the PIEZO1 protein and the liposome is diametrically opposed, the force generated between the membrane and the protein becomes larger, and PIEZO1 is flattened (the second line of the figure above).
Finally, the researchers obtained two structures of PIEZO1's convergence state and force flattening on the membrane, supporting the above conjecture.
That is to say, piezo1 protein has reversible deformation, and bioelectric signals are generated through the state of "one sheet and one combination" when forced.
△ The left is the convergence, and the right is the unfolding
Taking it a step closer, they revealed exactly how PIEZO1 could use its nanoscale curvature deformation to detect leather-scale forces (1pN=10-12N) as a class of low-energy ultrasensitive mechanical force receptors.
And this makes the author marvel at the beauty of the intersection of life processes and physical principles!
In simple terms:
In the resting state, the protein is in equilibrium (bowl surface area is 628 nm2, projection area is 314 nm2); when the membrane tension changes, the equilibrium is broken, and the membrane drives the PIEZO1 protein to flatten together.
Seeing the end, you may wonder, what is the use of studying it?
Of course, piezo has a very wide range of physiological and pathological functions (in the cardiovascular system, cardiomyocytes, and bone production and remodeling), and it is necessary to figure out its various mechanisms in order to carry out related drug design.
About the author
The common paper is Yang Xuzhong, Lin Chao, Chen Xudong and Li Shouqing, doctoral students from Tsinghua University and the University of Science and Technology of China.
The corresponding authors are Professor Xiao Bailong of the School of Pharmacy of Tsinghua University and Professor Li Xueming of the School of Life Sciences.
Xiao Bailong graduated from the Department of Biochemistry of Sun Yat-sen University with a bachelor's degree, graduated from the University of Calgary in Canada, and 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 achievement PIEZO.
He is currently a long-term professor and doctoral supervisor of the School of Pharmacy of Tsinghua University, and a recipient of the National Science Foundation for Outstanding Young People.
Xueming Li graduated from the University of Science and Technology Beijing with a Ph.D. from the Institute of Physics of the Chinese Academy of Sciences and did four years of postdoctoral research at the University of California, San Francisco.
He is currently an associate professor at the School of Life Sciences of Tsinghua University, a researcher at the Tsinghua Peking University Joint Center for Life Sciences, the Center for High-tech Innovation in Structural Biology, and the Frontier Research Center for Biological Structures.
In recent years, his research interests have been mainly to introduce a number of technologies such as deep learning and particle filtering into the field of cryo-EM.
Xiao Bailong and Li Xueming have been collaborating on PIEZO protein research for many years, and have published a number of results before this achievement.
△ The source of the WeChat public account of the School of Pharmacy of Tsinghua University
For more details on this study, interested readers are welcome to check out the original article~
Address of thesis:
https://www.nature.com/articles/s41586-022-04574-8
Reference Links:
https://mp.weixin.qq.com/s/pI_sLUv6IVnvwafakX61wQ