The Second Half of the Genetic Code

Interview with Paula Booth, professor of biochemistry at the University of Bristol

9. 10. 2013 | Paula Booth uses natural and synthetic systems to understand how membrane proteins fold and operate. In her research, she also tackles problems like antibiotic resistance.
AcademiaNet: Integral membrane proteins account for about 30 percent of all cell proteins. What is the role of membrane proteins in how cells work?

Prof. Paula Booth
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Prof. Paula Booth
Prof. Paula Booth: All cells have a membrane boundary to keep their contents separated from the outside. The proteins in the membrane are responsible for the transport of nutrients into cells and waste out of cells; they also act as receptors and signal transducers to allow information to get in and out of cells.
Then, inside cells there are further compartments that are membrane-bound. The proteins in the membranes of these compartments do a host of things: they make ATP that transports chemical energy within cells for its metabolism, for example, and they are involved in cell respiration.

Correct folding of these membrane proteins is crucial for cell function. Why is it important for us to understand how membrane proteins fold?

Understanding protein folding used to be called "solving the second half of the genetic code". A gene will tell you in what order to put amino acids and what protein you're going to get. But it doesn't tell you the three dimensional structure and function of the protein, which is how that string of amino acids folds up into one precise structure without forming knots or making mistakes. If a protein is unable to fold into specific, three dimensional shape, it will not be biologically active. In addition, misfolding can lead to protein malfunction and disease.

Membrane proteins traditionally haven't been studied, I guess people thought it was too hard. I've always tried to work on membrane proteins because I used to work in photosynthesis, which involves huge membrane proteins that assemble in a very particular way so that you get really efficient light energy absorption. We're trying to figure out ways to understand how these proteins fold and how we can control the folding so that we can make use of it. The more you understand about a system, the easier it is for you to interfere with that mechanism and stop things happening. What we desperately need to do is to understand the fundamental mechanisms of what's going on in the cells. Then once you've got a picture you can then decide what you're going to do with it.
Synthesis of a membrane protein
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(© Paula Booth)

Synthesis of a membrane protein | Ribosomes are like protein factories: this ribosome (orange) binds to a protein channel in the cell membrane (purple) and uses mRNA (red) to synthesise a membrane protein.

One of the main things your study group looks at is membrane protein folding mechanisms and the role of the membrane lipids in regulating folding and membrane protein activity. How does the lipid environment affect how membrane proteins fold and perform their functions?

The lipid environment is very different to just being in water, like most proteins inside the cell. The lipid membrane affects how the proteins come together in two dimensional interactions, and it must affect how they fold, but no one has really looked at that in detail. However, there is some interesting work coming out to say that if you haven't got the right lipids, then the proteins might fold into the wrong confirmation.

What particular proteins are you investigating at present?

Mostly we're looking at transporters, we're working at the moment on one that acts as a sugar transporter. These proteins are called major facilitator transporters and they're responsible for all glucose transport in humans. They also transport drugs and have a role in antibiotic resistance, which is a huge problem in TB and in cancer therapy. These proteins are somehow upregulated when cells become resistant to antibiotics and will just pump the drugs out of the cell.

If you could paralyse the proteins that are involved and stop them pumping the drugs out, you might be able to understand and stop antibiotic resistance. But the proteins are not the only factor involved. There are a whole load of other things involved in allowing a bacterial cell to become resistant to a drug, so there must be other levels of drug recognition going on.

You also do a lot of work in synthetic systems, where you create artificial membrane modules. How do you use these systems to understand protein folding?

We use synthetic systems to help us to understand what happens in the cell, how proteins actually fold in the cell. If you try to use cells themselves, you just can't get the right level of information. We can manipulate the lipid membrane boundaries we make quite readily to understand their properties and get some sort of idea about how that might affect what the proteins do.

We're also trying to build very basic synthetic cells, where we make lipid boundaries, put proteins in, and try to control the assembly of the protein. What we're doing initially is allowing reactants to go inside our synthetic cell and react to make a particular product. We've been trying to use light activated molecules, which we either put in the membrane or attach to the protein. Then we can zap the sample with light to make the protein open and close, and to control the assembly of the protein. So we've done quite a lot of work on that, which has gone pretty well.

Where do you see your research going in the future? Do you think making the synthetic cells is going to be the big focus?

I suspect what we'll end up doing is using bigger synthetic systems that have more of the biological machinery inside them, trying to understand which bits of biology are important and which aren't. That will be difficult though, because there are so many components in biology and we don't know which ones we'll need, so we may always be too artificial. In the future we will probably start putting genes inside our systems as well, but at the moment we've just been trying to build an artificial synthetic outer construction, without worrying about genes.

Dear Prof. Booth, thank you very much for this interview.

Interview: Helen Jaques   (© AcademiaNet)

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