Q&A: Professor Helen Saibil

26 March 2009

To work properly, proteins must fold into the correct 3D structure; misfolding can have catastrophic consequences for organisms. Helping to unravel this complex process is Professor Helen Saibil from Birkbeck, University of London. With colleagues, she has published the first structure of a newly folded protein just before it is released from a chaperonin complex, a type of chaperone that is required for protein folding in all cells.

How did this work start?
In the early 1990s we started working with crystallographers on the structure of GroEL, a chaperonin found in Escherichia coli that works with another chaperonin, GroES, to fold newly made proteins and refold those that have been damaged by stress. In 1994 we published a first, blurred image of a model protein held in the cavity of GroEL, and since then we’ve been trying to get a more detailed image of what a folding protein looks like in there.

What challenges did you face?
Unfolded proteins aren’t proper structures - they are extremely disordered and variable. Single-particle electron microscopy relies on averaging many different views, and if you average together views of unfolded proteins, the structure just blurs out. We also found that the protein complex stuck on the microscope grid in the wrong way, so we couldn’t get all the 3D information on its structure. After quite a few years’ effort, a couple of things happened that helped us: our US collaborators found a way to modify the outside surface of GroEL so it could lie on the grid in a way that meant we could get side views of Q&A the protein; and a colleague developed statistical methods to ‘sort out’ the imaging of disordered, variable structures.

What’s new for this paper?
The Nature paper is a big step forward: it’s the first time we’ve been able to show a protein actually inside the folding chamber, just before it is released. We studied a protein called gp23, which forms the shell of the T4 bacteriophage. Folding in T4 requires GroEL and a T4-specific version of GroES, which is taller than the E. coli form, because - it was thought - gp23 is so big. We found that, to our delight, that this was the case; we showed that gp23 is absolutely wedged inside the folding chamber.

What can this research tell us?
Understanding cellular protein folding is important: if misfolded proteins accumulate they aggregate and cause serious, nontreatable misfolding diseases such as Alzheimer’s. Chaperonins are one of the major components of the protein-folding system. They are activated under stress and their activation seems to deteriorate with ageing, which is why many proteinmisfolding diseases occur in old age.

How has the Trust helped you?
I’ve been supported by the Trust for many years, and recently completed a yearlong sabbatical at EMBL [the European Molecular Biology Laboratory] in Heidelberg, supported by a Trust Flexible Travel Award. During that time I worked on cryo-electron microscopy of frozen cell sections, a very recently developed technique that makes it possible to cut sections of unfixed, frozen cells or tissues. This method allows you to look at cells and organelles closer to their native state than conventional electron microscopy does. I was keen to get back to lab work, which I never have time to do in my own lab, and the experience was tremendous. I ended up working on a yeast prion model system, and have since secured a Trust infrastructure grant to purchase equipment to permit this kind of work in my own lab.

What do you do outside of the lab?
I enjoy swimming and walking, as well as the visual arts and music.

Reference

Clare DK et al. Chaperonin complex with a newly folded protein encapsulated in the folding chamber. Nature 2009;457(7225):107-10.