Tsinghua scholars put forward the delicate mechanism of cell "perception" of mechanical forces.

Cell perception of external signals is a basic biological requirement, one of the most important is the perception of mechanical forces.
such as hearing and touch, lung perception of dilation, vascular wall perception of blood flow, many physiological processes are related to the perception of mechanical forces.
some specialized cells evolved into "terminals" specialized in sensory mechanical forces, such as inner ear hair cells, ontoosensory neurons, and so on, which are usually very sensitive to mechanical forces.
not only, most cells contain structures that sense mechanical forces, which are important for functions such as cell migration, amplification, and differentiation.
cells' "perception" of mechanical forces needs to be translated into cellularly recognizable biological signals, usually by ion channels and cell membrane receptors, as well as intracellular signaling pathways.
as early as 1979, The California Institute of Technology's Hudspeth (now a professor at Rockefeller University) and Corey (later at Harvard University) speculated that mechanical stimulation might be conducted by ion-generated electrical currents through experiments in the audible epithelial cells of bullfrogs, since sub-millisecond signals could not be transmitted by traditional second messengers.
2010, the Ardem Patapoutian Laboratory at the Scripps Research Institute in the United States found that the Two genes Piezo1 and Piezo2 are essential components of the gene encoding the mechanical gated cation channels of mammalian bodies.
later studies found that Piezo1 and Piezo2 belonged to a very conservative class of mechanically gated cation channels that playamy properties in a variety of physiological processes, including tactile, pain, breathing, ontobody sensation and vascular development (Figure 1).
these genetic mutations in the human body can lead to diseases such as red blood cell cognac syndrome, distant joint distortion, congenital lymphatic misdevelopment and tactile loss, showing their importance.
the predicted structure, these proteins are not much like any other known protein, and they appear to be very large compared to other ion channels (more than 2,000 amino acids).
Dr. Xiao Bailong, a researcher at Tsinghua University's School of Pharmacy, and his colleagues demonstrated for the first time that the Piezo protein forms mechanical gated cation channels during his postdoctoral work at Professor Ardem Patapoutian's lab, which was first identified in mammalian cells, but its specific mechanism of action is not clear. The three-dimensional structure of
proteins often helps scientists explain their function.
2015, Tsinghua University's Gaoning group, Xiao Bailong's team and Yang Maojun's team worked together in nature magazine to report on the piezo1 channel medium-resolution frozen electric mirror 3D structure, revealing its three-leaf propeller-like three-dimensional structural characteristics, providing an important clue for the analysis of its molecular mechanism.
2016, Xiao Bailong's team published an article in the journal Neuron, reporting on the amino acid composition of the Piezo1 channel responsible for ion permeability and selective tunnel zone modules and mechanical sensing modules responsible for mechanical force sensation and conduction, and for the first time to propose the hypothesis that the Piezo1 channel exercises its mechanical gated ion channel function in a modular way.
2017, Xiao Bailong's team further reported on the new regulatory protein SERCA2 of the Piezo channel in the journal Nature-Communications, and systematically expounded its effect on the mechanism of the activity regulation of the Piezo protein channel, providing important clues for the development of potential drugs based on this protein interdonosis regulatory model.
on Tuesday, Nature published a study by Tsinghua University's Xiao Bailong and Li Xueming's team entitled "Structure and Mechanogating Mechanism of The Piezo1 1 Channel".
this study analyzes the high-resolution three-dimensional structure of the mammalian mechanical gated Piezo1 ion channel, reveals the key functional sites involved in mechanical force perception and transmission, and then for the first time puts forward the delicate working mechanism of the Piezo channel for mechanical gating with similar leverage principle.
noteworthy, the Ardem Patapoutian laboratory, which originally discovered the Piezo1 and Piezo2 genes, also worked with the Andrew Ward Laboratory at the Scripps Research Institute, almost simultaneously publishing the high-resolution structure of Piezo1 in the journal Nature.
The high-resolution structure of Piezo1 was also published in the journal eLife by the Roderick MacKinnon Laboratory at Rockefeller University.
the Piezo 1 channel presents a three-leaf propeller structure of the triple-poly(Figure 2a), the center of the control ion permeable center of about 350 amino acids at the base end, and the 2,200 amino acids at the amino base that form the peripheral characteristic shaded domain, including the blade, the "beam" and the anchor area (Anchor 2a-c).
Although the Piezo1 protein does not contain repetitive sequences, Xiao Bailong and other scholars were surprised to find that its peripheral blade shaving spartauny is made up of a total of nine repetitive structural units based on four transmembrane regions.
they named this characteristic domain TransnotiHelical Unit (THU), which also happens to be an acronym for Tsinghua University.
in the paper by Ardem Patapoutian and Andrew Ward, this structure is named Piezo repeats.
in the topological structure, the Piezo1 protein is assembled into a class of membrane protein complex (Figure 2b-c) with 38 cross-membrane regions per subkey and a total of 114 spans.
in the intracellular part of the three-dimensional structure, there is a characteristic beam structure of about 90 s, which connects the remote blade area to the CTD and anchor domain of the central hole area (Figure 2b-c).
Xiao Bailong thinks this is an important structural basis for the Piezo channel to effectively transmit the perceived mechanical force changes of the peripheral blade part to the central channel section.
structure shows that there is an uneven relative displacement in the beam region, i.e. the motion displacement at the far end is larger, while the near-central hole-in-the-hole region shows only a slight displacement change.
, the refore, the conformation change of the Piezo1 structure fits the principle of leverage.
their electrophysiological function research data further supporttheir its proposed mechanism of mechanical force perception using leverage in the Piezo1 channel. Dr.
Xiao Bailong told The Intellectuals that the above research results strongly promote the understanding of the structural characteristics and molecular mechanisms of the Piezo channel.
they also found that Many of the amino acid mutations associated with human genetic diseases, such as The piezo1 and Piezo2 gene mutations that cause red blood cell cognac syndrome and distant joint distortion, respectively, focus on the interaction interface of beam-CTD-Anchor, providing important clues for the next step in understanding how these genetic mutations lead to Piezo channel dysfunction.
Source: Wang Chengzhi.