Touch the Pressure Sensor

The revealing structure of one pressure-sensing protein complex.

The sensation of touch is perhaps the most elemental, and the most wide-spread, in nature. And detecting pressure doesn't just function in conscious sensation, but in all sorts of other processes such as, proprioception in muscles and joints, kidney function, red blood cell shape maintenance, blood pressure regulation, pain, bone maintenance, cancer cell invasion, neural development, and embryonic development generally, where bulging, shape changes, and migration are all guided by mechanisms that sense pressure inside and between cells.

Thus it is no surprise that we have numerous pressure sensors in our genomes, of various types. The sensors involved in hearing (TMC1 and TMC2) are different from a series of sensors involved in touch, (TREK-1), which are different from those responsible for organ shape and development. One thing they all share, however, is that they are cation channels. That means that deformations in the membrane they lie in, or other attachments they may have, get translated into a rush of potassium or calcium ions, out of or into the cell, respectively. This leads either to direct membrane depolarization (potassium ions), or signal propagation (calcium) via other proteins and channels.

A recent paper (review) detailed the interesting structure of PIEZO1, which is in a recently-discovered family of mechano-sensors that function in organ development and maintenance, conduct cations, mostly potassium, when activated, and directly (though briefly) depolarize membranes they reside in. While all membrane proteins are affected by membrane stretching, and there are simpler ways to translate mechanical stress into channel opening, PIEZO1 shows a rather intricate structure that allows exquisite sensitivity and control of its channel.

Top view, and side views of the PIEZO1 mechanosensory ion channel. In cells, the top faces the cytoplasm.

The first thing to notice is the dramatic, classic, maybe even Star-Treky, triskelion structure adopted by the trimeric protein. The authors note that they did not even see the entire protein, and that there should be twelve more helices extending out on each arm beyond those here that we can see, which are flapping in the breeze, so to speak. Second is the knot of protein in the center, above the plane of the rest of the structure. The actual channel is deep within the convergence zone of the three arms, so is far away from the protein knot, which extends intracellularly. This structure was derived from electron microscopy, which has begun to overtake X-ray crystallography as a method for structure determination, and the authors provide an averaged overview of what they were looking at, below.

Averaged electron micrographic view, without the inferred atomic modeling shown above. Scale bar is 10 nm.

Here, the arms are looking much more like a membrane interface, and the structure as whole clearly forms a cup that pre-deforms the membrane in a way that then makes the detection of membrane stretching even more sensitive than it would otherwise be. The authors spend much of the paper showing that this is the case- that in artificial vesicles, one can see PIEZO1 deforming the local membrane quite dramatically. One can easily see how this would make membrane stresses easier to sense.

Model of the channel (gray) surrounded by key protein structures, including negatively charged Glutamic acid (E) at the most constricted point, where opening is predicted upon membrane tension.

As for the actual channel, they provide a structure that narrows down to nothing at the bottom (E2537, showing the red negatively charged ends of glutamic acid). Clearly their model is of a closed version, which makes sense given the relaxed conditions used for visualization. Opening awaits some stretch on the overall structure that will pull these protein structures apart slightly, but not too much- enough to allow a four Ångstrom opening, as estimated from studies of the channel's conductance.

Another key part of the structure is the long helix running from the bottom, near the ion channel to about halfway along each triskelion arm. They seem to be key "beams" that transmit leverage from tension-induced membrane flattening towards the center nexus where this channel constriction is so obvious. As the authors put it ("TM" refers to transmembrane alpha helix domain, of which there are 38 in all per monomer):

"At first consideration a force directed along the triskelion arms toward the center of the trimer, associated with flattening of Piezo’s arms, might be expected to constrict the pore further. However, given that TM37-38 are domain-swapped relative to TM1-36, such a force will more likely push the ‘swapped’ pore-lining helices away from the center and open the pore."

That is to say, the beam helices at so long and subtly connected to the pore that they push cross-wise from the three directions, pulling the channel open instead of pushing it closed. This putative mechanism helps to some degree also to isolate the pore from the activating force, limiting its opening so that it can be ion-selective and have high, but limited, conductivity while open, all with super-high sensitivity. There are examples of stretch activated channels from bacteria whose function is to relieve turgor pressure stress, and whose opening is virtually unlimited under stress, becoming completely non-selective in what they allow through, which is very effective for their stress-relieving role.

This is a beautiful and informative structure. It shows yet again that underlying the magic and mysteries of biology is always structure and chemistry. Defects in these types of channels are responsible for a wide range of problems. Complete deletion of this gene (PIEZO1) in mice is rapidly lethal soon after the heart begins to beat, since the nascent vasculature is deranged, not being able to sense fluid pressures. The same gene is key for neural cell development and pathfinding. It also plays a central role in helping red blood cells know and regulate their pressure status, which is key to their function and survival as they squeeze through tight spots and get jostled by turbulent flows.

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