Hydrophobic signal transduction

This is the first of two blogposts I'm writing about signal transduction in the cell. In this post, I am focusing on signal transduction using hydrophobic signalling molecules, as well as a brief introduction to the structure of a cell membrane. 

Put simply, hydrophobic molecules can pass through a cell membrane without issue, since the membrane consists of a lipid bilayer which is also hydrophobic. That means the molecule can then bind to a nuclear receptor. More on that in a bit.

Cell membrane structure 

Every cell has a cell membrane...obviously. The job of a cell membrane is to keep all the important parts of the cell, such as the nucleus and mitochondria, inside the cell, whilst also regulating what goes in and out of the cell. 

The basic structure of a cell membrane is that of a lipid bilayer - in effect, two strands of glyceorphospholipids. A glycerophospholipid is just a phospholipid bound to a glycerol backbone; a phosopholipid, meanwhile, comprises the bulk of a lipid bilayer.

Phospholipids consist of three key parts:

• Two strands of fatty acids
• which are bound to a phopshate group
• which is bound to a substituent. 

Those fatty acids make up a hydrophobic tail, whereas the phosphate and headgroup make up a polar headgroup. Therefore, along a lipid bilayer, you'll have both a wettable surface, where water molecules can interact, as well as a hydrophobic surface, which is resistant to water. At this hydrophobic surface, water molecules tend to form clathrates (lattice structures) with each other, since they're unable to interact with the hydrophobic tail.

Earlier, I mentioned a subsitutuent group bound to the phosphate; there are several possible substituents, namely choline, ethanolamine, and inositol - all of these are alcohols, however membranes tend to stick to only a few different options. 

Hydrophobic signal transduction

If a molecule is small, uncharged, or non-polar, it can pass through the lipid bilayer, no problem. This means that hydrophobic molecules can pass straight through into the cytosol (one of the liquids that exists in the cell). However, they'll still have poor solubility within the cytosol, so they'll have to bind to cytosolic proteins, like nuclear receptors, to get their message across.

The lac operon

A "simple" example of a regulatory system is a lac operon, which codes for various important enzymes in lactose metabolism. Here, you would use a metabolite as the signalling molecule, in this case lactose. A lac operon responds to lactose availability - no lactose, no metabolism through the lac operon.

First, it's worth clarifying what lactose is: it's a disaccharide of galactose and glucose molecules, connected through an ether link, and the lac operon will recognise the galactose and enable the metabolism to occur. That's important because if you wanted to mimic the lac operon's activity, you'd use IPTG, which is an analogue of galactose. Why would that be an issue, you ask? It's because the galactose can be digested by enzymes, and IPTG can't be hydrolysed or digested; this enables you to interfere the process.

And this is the process: 

• Along a lac operon is a sequence of DNA, where transcription of DNA may occur, should polymerase be available to act. 
• However, at low concentrations of lactose, there may be a repressor protein that's bound to the DNA, blocking the polymerase. 
• But as soon as lactose binds to the repressor. it will induce a conformational change within the repressor, causing it to stop binding to the DNA, and the polymerase can act. 
• The lac operon can then act, meaning the enzymes will be activated and start metabolising. 

And yes, this is a massive oversimplification, but if I went any further in detail, it would stop being a study post and start being biology coursework.

The eukaryotic nuclear receptor 

The lac operon only exists in bacteria, but when it comes to eukaryotes, there are nonetheless many examples of nuclear receptors used in DNA transcripton. The nuclear receptor here will have a few domains:

• An activation domain, responsible for activation transcription.
• A DNA-binding domain
• A ligand-binding domain

The process is "simple":

• A ligand would bind to the ligand-binding domain. An example of a ligand might be a hydrophobic molecule such as a steroid.
• We will then have an activator binding to the activation domain, and this will act as a regulator of sorts. Only once the activator has bound can the polymerase molecule interact.

One example I've been taught is that of cortisol. Cortisol is a stress hormone, and it would bind to a glucocorticoid receptor, which has all the domains I mentioned earlier, specifically to the ligand-binding domain. This receptor can dimerise with another receptor and form a homodimer, where cortisol can then also bind to the other receptor. The receptors in the homodimer are a specific distance apart, and can only bind at specific points along the DNA - at any other positions, binding will not happen. But we can also have heterodimers, where two different ligands bind to receptors that then dimerise, which will then result in two different signalling responses.

This whole process is relatively slow; hormones are transported this way, and you might be aware that hormones are used for long-term signalling. Take estrogen and testosterone, which are sex hormones; puberty lasts over several years, it isn't immediate.

And that's all there is to hydrophobic signalling...at least all I need to know for now. The next post will cover hydrophilic signalling, including ion channels and transporters, so you can look forward to that anytime soon.