A lot of what makes us Human relates to the way we perceive the world around us. Our senses are vital in guiding our interactions with objects, the environment and each other. The way we receive and interpret senses such as touch, smell and sight essentially determines how we act and communicate. We usually think of these senses on a physiological level - the pressure exerted on our skin by objects, a tempting scent entering our nostrils - but the effects of these sensations can also be considered at much smaller scales. There are proteins that recognise and respond to physical sensations at a molecular level, responding to stimuli that directly affects our cells.
The importance of these molecules led to the award of the to David Juliu and Ardem Patapoutian for their groundbreaking work in thermal and mechanical transducers. What do we know about these molecular sensors and how can it help us to understand our own perceptions of the world around us?
The hustle and bustle of cells
Mechanotransduction, the process in which a physical stimulus is transferred to a biological response, is important in a number of cellular processes. This includes mechanical effects on cell movement and adhesion, but also in cell communication, with knock-on effects transferred through molecular pathways. In the crowded environment between cells, called the extracellular matrix (ECM), there is a constant barrage of forces exerted on the cells. These external impacts are received by a diverse range of mechanosensitive molecules, including ion channels and receptors, which pass these mechanical stimuli on through molecular signals. Have you ever wondered how these tiny molecules turn mechanical force into biological change?
Squeezing shut molecular channels
One type of molecule involved in mechanotransduction are mechanosensitive (MS) ion channels. These are protein complexes found in the cell membrane which are acted upon by an external force, causing the channels to be squeezed shut, restricting the flow of ions across the membrane. In this way, they are directly turning physical stimuli into chemical responses, triggering subsequent biological pathways. These changes in ion concentration across the membrane can be monitored by tracking the change in current while force is applied to the cell sample. By applying forces to cells using specialised equipment, researchers can explore the impact this has on the movement of ions across the membrane.
Piezo1
Piezo1 is an MS channel, involved in processes that respond to varying sensations, including touch and pain. These protein complexes are comparatively large for ion channels, comprising over 2,000 amino acids. Like other MS channels, Piezo1 complexes form ion channels which are physically closed, or squeezed, by mechanical forces driven by membrane tension effects. In 2018, Arde Patapoutian and colleagues obtained a higher resolution of the structure of Piezo1 using cryo-Electron Microscopy (cryoEM), which gave a much clearer picture of what these ion channels look like. With this information there is now a better understanding of how these ion channels adapt to physical forces to control biological responses.
The Piezo1 complexes are formed of three copies of the protein (homo-trimer), forming a three-bladed propeller-like structure. Rather than the ‘propeller� spinning like it might on a plane engine, instead this propeller sits within the cell membrane, forming a large anchor point for the remainder of the complex. Above the central axis of the propeller, outside the cell membrane, is the ‘cap� domain, loosely connected to the remainder of the complex and suggested to have some role in blocking or limiting ion movement.
However, it is the central section of the propeller that appears most important for the mechanosensing function of the complex. The central pore, through which the ions can move across the membrane, is formed by an ‘inner� and ‘outer� helix from each of the three protein copies. These inner and outer helices are further surrounded by repeating helical bundles, referred to as Piezo repeats, however these follow on from the neighbouring protein of the trimer, known as ‘domain swapping�. These helical regions are connected together via additional ‘beam� and ‘latch� domains which link the inner and outer parts of the propeller structure. It is thought that these Piezo repeats and their connectivity is vital in translating the changes in membrane tension to the opening and closing of the ion channel.
Mechanosensing in action
More recent work on determining the structure of Piezo1 led to the determination of two different conformations of the channel in the lipid membrane. These conformations represent a ‘bent� conformation, much like the original Piezo1 structure above, along with a ‘flattened� conformation. Though these conformations do not exactly correlate with the expected membrane effects in response to mechanical force, they do give a potential mechanism for how changes in membrane tension could affect the structure of the channel. There is a significant movement of the propeller ‘blades� between the two conformation, which translates to a smaller rotation of the inner helices relative to each other. This could indicate how the large forces exerted on the cell membrane can be translated to a molecular response to allow subtle changes in the channel pore and affect the flow of ions across the membrane.
A video demonstrating the ‘bent� () and ‘flattened� () conformations of the Piezo1 channel. The first part of the video shows the full structure, switching between the two conformations, while the second part displays a cut-out view, focusing on the inner helices and their changes between the two conformations. Structure visualisations created using .
As the structures highlighted above show, the current understanding of Piezo1 channels has progressed significantly through the development of cryoEM as a structure determination technique. With continuing improvement in this field, and the increased ability for researchers to view these structures within whole cells, our understanding of these complexes should continue to grow. Perhaps soon we will be able to see in detail the impacts of these external forces on the Piezo1 structure and really see how force can affect function.
David Armstrong
Artwork
The artwork for this featured article was created by Hiyori Ikeda, a year 7 student at . The Piezo1 protein and its relationship to touch and sensation, inspired Hiyori to explore the sense of touch. She wanted to visualise what it is like to touch various objects, and how the different sensations can trigger different feelings. The artwork, created on paper using ink and pencils, shows a pair of hands holding a rope-like thread that represents the protein chain of Piezo1, surrounded by various objects that relate to the sensation of touch. Hiyori even incorporated a small copy of the Piezo1 channel itself, in the centre of the piece, to bring in the inspiration for her artwork.
View the artwork in the .
Relevant structures:
Relevant publications:
Saotome K, Murthy SE, Kefauver JM, et al. Structure of the mechanically activated ion channel Piezo1. Nature. 2018 Feb;554(7693):481-486. DOI: 10.1038/nature25453. PMID: 29261642; PMCID: PMC6010196. []
Yang X, Lin C, Chen X, et al. Structure deformation and curvature sensing of PIEZO1 in lipid membranes. Nature. 2022 Apr;604(7905):377-383. DOI: 10.1038/s41586-022-04574-8. PMID: 35388220. []
Ridone P, Vassalli M, Martinac B. Piezo1 mechanosensitive channels: what are they and why are they important. Biophysical Reviews. 2019 Oct;11(5):795-805. DOI: 10.1007/s12551-019-00584-5. PMID: 31494839; PMCID: PMC6815293. []
Jin P, Jan LY, Jan YN. Mechanosensitive Ion Channels: Structural Features Relevant to Mechanotransduction Mechanisms. Annual Review of Neuroscience. 2020 Jul;43:207-229. DOI: 10.1146/annurev-neuro-070918-050509. PMID: 32084327. []
Martinac B. 2021 Nobel Prize for mechanosensory transduction. Biophysical Reviews. 2022 Feb;14(1):15-20. DOI: 10.1007/s12551-022-00935-9. PMID: 35340591; PMCID: PMC8921412. []
Martino F, Perestrelo AR, Vinarský V, Pagliari S, Forte G. Cellular Mechanotransduction: From Tension to Function. Frontiers in Physiology. 2018 ;9:824. DOI: 10.3389/fphys.2018.00824. PMID: 30026699; PMCID: PMC6041413. []
Paluch EK, Nelson CM, Biais N, et al. Mechanotransduction: use the force(s). BMC Biology. 2015 Jul;13:47. DOI: 10.1186/s12915-015-0150-4. PMID: 26141078; PMCID: PMC4491211. []
