What are proteins?

We usually think of protein as something on our plate. Chicken. Tofu. Perhaps a gym supplement. But what if I told you proteins are so much more? They’re the tools life uses to get anything done – breathing, thinking, healing, and growing. And inside you right now, there are tens of thousands of different proteins, all doing specialised jobs, all working together like a molecular orchestra.

Proteins are polymers, like plastics: massive molecules made from chains of smaller building blocks called amino acids. Think of them like beads on a string – except instead of just one type of bead, nature uses any number from a set of 20 different amino acid “beads”, which can be placed in any order. The specific order they're arranged in is determined by our genes, which act as recipes coding for the protein amino acid sequence. And because each amino acid has a unique shape and chemical properties, the amino acids that make up a protein, and the order they come in, dictates how the protein folds into its final 3D shape. And that shape is essential. It decides what the protein can do, where it fits in the body, and how it interacts with other molecules to perform its function.

One of the most important proteins we know about – insulin – was first decoded right here in Cambridge, and it changed how we understand life by figuring out which amino acids were present.

Later, from the amino acid sequence, we figured out the 3D structure of proteins like insulin and haemoglobin – the actual shape they fold into – which is crucial, because in the world of proteins, shape is everything. If a protein doesn’t fold correctly, it can’t do its job. And when that job is regulating blood sugar, as insulin does, or carrying oxygen around the body as haemoglobin does, then things get serious.

So, in this first part of the programme, we're diving into what proteins really are – not just nutrients, but the biological machines that run our bodies. Here’s Sir Alan Fersht, a protein chemist at the MRC Laboratory of Molecular Biology at Cambridge University…

Alan - Proteins are the workhorses of the cell. Somebody once described them as being where the rubber hits the road. And that's because virtually every chemical reaction in the body is catalysed by an enzyme from the dissolving of carbon dioxide to the synthesis of our genes. They're responsible for the structure of our body. Muscles are protein, hair is a protein. They're also responsible for the defense of the body. Antibodies, which are important in defending us against disease, are proteins. So what are they made of? Proteins are essentially chains of simple molecules called amino acids linked together to form sometimes short and sometimes very long chains.

Marushka - Can you tell us why a protein structure is so important to how it works?

Alan - What is important about a protein is basically its shape, its three-dimensional structure. What proteins have to do is to interact with other molecules in the cell. They do that like in, say, a key fitting a lock or two pieces of a jigsaw puzzle fitting together. So shape is very important for proteins to recognise other molecules. If something goes wrong, the shape changes, perhaps due to a mutation where amino acid residues in a protein are changed because of a mutation, or sometimes the structure gets a bit twisted, it can cause disease. So structural biology, which is the determination of the structure of proteins in three dimensions, has been a very important field.

Marushka - So as you mentioned, the key has to fit the lock with a protein. And insulin was one of the first proteins to be fully sequenced, meaning that it was the amino acid sequence was decoded. Why was this such an important breakthrough?

Alan - Insulin was the very first protein to have its sequence of amino acids determined, and that was done by Fred Sanger in 1954 in Cambridge. By sequencing, we mean the order in which the different amino acids join one to another. It was a tremendous breakthrough because until then, the structures of proteins in such a way were entirely unknown. And so it was one of the big breakthrough events in the last century in chemistry and biology. First of all, it showed that proteins had a defined structure, which you could determine, and just not a mystery. And it laid the foundations for modern molecular biology and biochemistry. The three-dimensional structures of proteins were first determined again in Cambridge at the MRC Laboratory of Molecular Biology. And in order to do that, people had to use various complex techniques, but they had to know the amino acids in the protein to solve that three-dimensional structure.

Marushka - So once the linear structure has been decoded, so the amino acid sequence, and we've got the 2D structure, we're then able to find the 3D structure for proteins such as haemoglobin. Why was finding the 3D structure so important in biology?

Alan - The three-dimensional structure of haemoglobin was determined by Max Perutz. It first of all showed us in detail what a protein looked like, and it also showed us how the different amino acid residues in the protein contributed to its function, how it worked. But it also set up the whole area of understanding many diseases, which are caused by mutations. As I mentioned earlier, mutations in proteins are the change of one amino acid residue to another because of effects of radiation and chemicals and things like that affecting our genes. And there are diseases such as sickle cell anaemia that occur just because of a single mutation. And Max Perutz's experiment was able to show this and explain it. That led to the whole area of looking at proteins to understand how mutations could cause disease and to help us think of ways of how to cure diseases because we knew the structure of the protein. So haemoglobin, apart from initiating the whole area of structural biology, it also set up the idea of having structure-based drug design, where you looked at a protein and you tried using computers and chemistry to make molecules to cure those diseases.

Marushka - So to end off, can you tell us about how much proteins influence our body? What types of diseases that they are involved in, showing why they're so important to study their 3D structure, not just to understand the disease, but also to solve the disease and to find cures for the disease?

Alan - There are many diseases that are caused by just tiny changes in a protein, simple mutations that change one amino acid residue to another. Tay-Sachs disease is an example of a single mutation causing a disease. Cystic fibrosis, another. And at a more general level, cancer is a disease of mutation. There are proteins that control the cell cycle, whether or not it's going to replicate, proliferate, or whether it stays as it is. And there are proteins in the cell that act like accelerator pedals that tell the cell to reproduce. They can be turned on by a mutation. So the cell wants to replicate indefinitely. There are other proteins that are brakes that try and stop it, and mutations can stop them doing that. And these mutations cause cancer. And by looking at those types of mutations, we can try and design drugs to get them working again properly.