Really Awesome Proteins: The Major Histocompatibility Complex

Part two in the RAP series is the major histocompatibility complex (MHC). This little protein really is brilliant. It’s a crucial part of your body’s defence against illness. If you think of your body like a battleground, and viruses or bacteria as bad-ass invaders, your immune system is your army. Complete with a full range of artillery and a stunning intelligence network. The MHC is part of that intelligence network.  

Almost all proteins have an expiry date, a time when they are ravaged by the stresses of cellular life and are frankly past their best. Since proteins are so crucial to life, it doesn’t do to have old shoddy proteins wobbling around performing their tasks in a half-arsed manner, like it’s permanently a Monday morning in your cells. Instead, the cell has a recycling system, where it breaks down proteins that are past their use-by date into fragments known as peptides. These peptides are attached to the MHC, and taken to the surface of the cell where they are displayed for all to see. Or, more relevantly, for receptors on the surface of T-cells to see. 

Most of the time, T-cell receptors recognise these peptides as being ‘self’ molecules, peptides that came from proteins of the body. However, if for example a virus hijacks the cell, there are viral protein floating around. And if these viral proteins need to be broken down, viral peptides will be displayed by the MHC on the cell surface. And T-cell receptors will spot them. At this point I like to imagine frantic flashing lights and alarms sounding CODE RED as the immune system springs into action to destroy the foreign invaders. You: 1, Virus: 0. Boom. 

So that’s one reason the MHC is really awesome, but there’s more. The MHC has extraordinary allelic polymorphic. This means that if you look around you in a crowded room, on a tube, at a concert, at anyone who isn’t your identical twin, you will see yourself surrounded by people who have different MHC genes to you. And to each other. This is actually really uncommon, most genes only have relatively few variations. There are three MHC genes though, HLA-A, HLA-B and HLA-DRB1 and there are around 1000, 1600 and 800 variations of these, respectively. That’s. A. Lot. Every person has in their genome just two variations of each of the three genes, which clearly means that the chances of any two people having the same final six are fairly slim. The result, a near unique MHC profile, unless you have an identical twin. 

This unique profile is the reason for tissue rejection in transplant operations. When the T-cell receptors recognise peptides, they’re not just seeing the peptide but the combination of MHC and peptide. They view them together, as a pair. If the cell is originally from a donor, the MHC will be slightly different, and the T-cell receptor will spot this too, and set off those alarm klaxons for destruction. Your body is pretty anti-anything that isn’t itself. The best way to avoid this tissue rejection is the get donor tissue from someone who is closely related to you, because you inherit your MHC gene variants, your siblings are the most likely to have a similar profile to you. I suppose being responsible for tissue rejection isn’t entirely really awesome, but the staggering variation in gene alleles is pretty damn mind-blowing. And it leads us to a question. 

Interactions between protein molecules are often quite specific, involving certain chemical groups reacting with others, in a specific environment. This is to prevent proteins from wandering around binding to everything they see, like teeny molecular floozies. Usually, in protein interactions, the side chains of the amino acids are the chemical groups that do the binding. These side chains are the groups that vary between the 20 different amino acids. 

However, the MHC can bind a nearly limitless variety of peptides that could include any combination of these side chains. How is it possible that six types of MHC molecule can bind and display so many different things? 

This is where the MHC really does get really awesome. It doesn’t bind the side chains; instead it interacts with the parts of the amino acid that are the same. Each end of the peptide is buried into a handy groove on the surface of the MHC molecule, and it is held there by interactions with its backbone, the constant chemical groups of the amino acids. The middle region of the peptide, which can be between 5 and 9 amino acids long, bulges outwards, waiting to be spotted by a scouting T-cell receptor. 

I don’t know about you, but I think that’s downright amazing. This one protein molecule can bind and display thousands upon thousands of peptides to your immune system, screening them for invading baddies like a highly efficient airport security system.  It has developed a way to be able to bind the maximum possible variety of different peptides, to be maximally efficient. Airport security could probably learn a lot from this bad boy. A genuinely Really Awesome Protein.