AUSTRALIAN FRONTIERS OF SCIENCE, 2008

The Shine Dome, Canberra, 21-22 February

Session 4: Getting into membranes
Chair: Professor Nick Dixon

Nick Dixon studied biochemistry at the University of Queensland, graduating with a PhD. After spending some years as a research fellow at the Research School of Chemistry (RSC) at the Australian National University (ANU), he won Fulbright and CJ Martin (NHMRC) Fellowships for postdoctoral study at the Department of Biochemistry at Stanford University School of Medicine. He returned to Australia as a Queen Elizabeth II Fellow in the Department of Biochemistry at the John Curtin School of Medical Research, ANU and was appointed Fellow in Biological Chemistry at RSC. In 2006 Nick took on a Professorship in Biological Chemistry at the University of Wollongong. He has been awarded an ARC Australian Professorial Fellowship to commence in 2008.

Proteins are the actors in cells. Genome sequencing has given us DNA sequences. DNA sequences encode sequences of proteins. And proteins are responsible for who we are, how we behave, why we get sick, how we recover from being sick or protect ourselves from being sick – and every aspect of the chemistry that governs our lives.

Proteins are polymers of generally 100 to 1000 amino acids (there are 20 different natural amino acids) and every protein sequence is different. This sequence specifies how they will fold up into a three-dimensional structure which, until about 10 or 15 years ago, was believed to be unique to each protein. This brings chemical groups on the surface together in such a way that each protein can then catalyse a chemical reaction or can interact and 'talk' with other proteins or other components in the cell to regulate development and disease and many other processes.

It would be obvious to you, then, that if we want to know how a protein works, or how it fails to work or malfunctions, it is important that we know what it really looks like. There is one technique that can give us high resolution atomic structural information on proteins. That technique is protein X-ray crystallography, where we produce a crystal of the protein in which each molecule is aligned in essentially the same way, or in one of several ways, and then we shine an X-ray beam on it and the beam is diffracted. This creates a pattern of intensities and positions of spots from which we can work backwards to determine the atomic structure of the protein.

The two speakers in this session are experts in this technique. They both come from Melbourne, which has become a Mecca for protein crystallographers over the last 10 or 15 years as this field has expanded enormously, in part as a result of genomic sequencing results but also as a result of improvements in technologies and improvements in the way that we can access proteins. For example, I tell my students that it is very hard to work on a protein that is only active in live human brains. That means that 30 or 40 years ago we would not have been able to work on such proteins, but these days, having the genes, we can make the proteins in abundant amounts in cells – animal cells, plant cells or bacterial cells – so we can access these kinds of important problems.

One of the reasons that Melbourne is the hub of crystallography in Australia is the recent commissioning of the Australian Synchrotron, just off the campus of Monash University. The synchrotron provides highly focused beams of high intensity X-rays that these guys can shine on their crystals so that they can look at ever smaller crystals and ever more weakly diffracting crystals, to extract protein structural information. Of course, the synchrotron is used in many other ways, but for us this is one of the major advantages in having it in Australia.

Our first speaker, James Whisstock, is known for his work over many years on serpins, a group of proteins that actually undergo big changes in their structure as they function. In a sense, his work on serpins and that of other people on related or analogous systems introduced a paradigm shift in protein biochemistry, where we realised for the first time that proteins weren't rigid molecules; actually, as they function and talk to other proteins, they often change structures between several different stable states.

That is not what James is going to talk about today. He is going to talk about several proteins with similar structures that are actually involved in two aspects of host-pathogen interaction. In this sense, it follows on from the session yesterday on plant host-pathogen interactions. These proteins mediate both the attack of the bacterial pathogen and the defence mechanism of the host.

Our second speaker, Galina Polekhina, is part of Michael Parker's group at St Vincent's Institute of Medical Research, in Melbourne, which is another large crystallography group in Australia that is producing wonderful work. She has been a key member of that team for the past 10 years and is now establishing her own independent research program.

She is going to talk to us on a related system in vertebrate defence against bacteria.