Bringing Structure to Biology
The poor diet and minimal exercise of a desk-bound bioinformatician has finally caught up. A rare bit of exercise brings on sharp pains in the chest, the sure sign of a blocked artery and ischemic heart disease. The image from our 2019 calendar for February illustrates one of the proteins via which your brain senses that pain.
Blocked arteries limit the amount of oxygen available to the organs they supply, and low oxygen levels result in acidification of the tissue and a drop in pH. Pain sensing nerves express one or more of six types of acid sensing ion channels (ASICs) in their membrane which detect this increase in protons.
Structures of ASICs (eg PDB entry 6ave) show them to be made up of three protein chains, each contributing two helices which span the membrane, and a large, multi-domain region on the outside of the cell (see figure 1). In a resting state, the six helices in the complex show no channel through the membrane, but when the pH drops, a large change takes place. Protons interact with a region distant from the membrane called the acidic pocket, causing it to change conformation. This shape change is propagated through to the transmembrane region which also changes its shape, opening a channel and allowing sodium ions into the nerve cell. An electrical signal is initiated by the sudden sodium influx, which ultimately becomes a nerve signal to alert the brain that you are in pain. The channel closes again in a fraction of a second in order to rebuild a concentration gradient of sodium across the neuron membrane. If the proton concentration remains high however, it does not reopen but adopts a ‘desensitised state’.
Figure 1. Ribbon diagram of a resting state ASIC (PDB entry 6ave). Each chain is coloured differently, the transmembrane region and acidic pocket are highlighted.
Dangerous animals target ASICs!
Structures in each of these three states (resting, open and desensitized) help explain how the channel works and could help us develop novel pain management drugs. Also helping us understand how the channel works, are naturally occurring molecules which can trap ASICs in certain states, these come in the form of toxins from a variety of animals.
The texas coral snake toxin MitTx binds to the extracellular domains of ASIC and traps it in the open state (e.g. PDB entry 4nty), causing intense pain. Maybe this is a defence mechanism, backing up the bright colours on the snake’s skin saying “don’t mess with me, it will really hurt”. Other toxins, such as psalmotoxin from the Trinidad chevron tarantula (e.g. PDB entries 4fz0 or 4fz1) bind to ASICs and stop pain signals (potentially so its prey doesn’t struggle so much as it’s being eaten!).
Structures of the open and resting states of the ASIC show that there are huge movements of the transmembrane helices between the two. In fact, the helices don’t just move, they break up and change completely how they interact.
Why though are there six different sorts of ASIC? They are not only involved in sensing pain, but also in transmitting pain signals though the nervous system. They are also involved in other sensory roles, such as taste and touch. So having several types, which can interact in different ways, gives a lot of scope for fine control over the nerve signal being sent.
About the Artwork
This image, a Silk batik by Tia D from Impington Village College, shows a trimeric ASIC channel in red, sitting in the grey nerve cell membrane. Its extracellular domain protrudes into the blue sea of the extracellular space. The inside of the cell is packed with other proteins, shown in pink.