Molecular chaperones are a set of families of proteins whose function is to help other proteins to fold, unfold and generally keep them out of mischief. When something goes wrong in protein folding, such as the unfortunate tendency to form aggregates, molecular chaperones have a distinctly important role to play.

One of the most studied of the molecular chaperones is the chaperonin family, a group of large, double-ringed proteins that form structures in which other proteins fold. The most commonly studied member is GroEL, an E.coli protein needed for bacteriophage growth. It acts in concert with a co-helper, GroES, to form a unique protein container in which polypeptide chains are safe to begin to fold free from contact with other proteins and the dangers of aggregation.

Professor Helen Saibil has been at the forefront of the study of GroEL and other molecular chaperones for the last two decades. A physicist by training who became fascinated with how living things worked, she has worked at Birkbeck College London for almost 20 years, arriving there after stints in Paris and Oxford, following her PhD at King's College London under the supervision of Maurice Wilkins.

Saibil admits that she didn't realise it was that Maurice Wilkins when she first applied to King's, but they quickly became firm friends, remaining so until his death in 2004. "He was working on photoreceptor membranes and I was working on the physics of how things worked in biology," Saibil says. "He was a lovely man, extremely nice. I ended up staying a long time at King's learning how to do all sorts of things."

Now at the School of Crystallography at Birkbeck and director of its Bloomsbury Centre for Structural Biology, Saibil didn't start off as an x-ray crystallographer. "I never did x-ray crystallography exactly - I started off in physics and then I moved into biophysics. I was interested in how things worked and I still am. Biophysics seemed to be the way to tackle the molecules and the machinery of living things, and so it was the topic that drew me in.

"Vision in particular was an area that attracted a lot of people from a physics background as it was a mixture of optics and biology and it seemed that it was all electrical - the way light went into the eye and activated currents. I was drawn to the subject and in the lab (at King's) they happened to be using x-ray scattering to study photoreceptor membranes. I ended up doing neutron scattering on photoreceptor membranes, looking at the distribution of a protein in the membrane. We were trying to understand how light is turned into a visual signal."

Then electron microscopy came along. By this time Saibil was at Birkbeck, where a colleague had grown the first crystals of GroEL. He encouraged her to have a look at them on the EM and she was entranced. "I could see from the images that it must be possible to find out a lot from EM but I didn't know how at that time. It looked like something that I could really get my teeth into. I've been working on it ever since."

Lid on the box

GroEL is part of the heat shock protein (Hsp) 60 system, responsible for assisting protein folding. It is a hugely abundant protein in E.coli, often overexpressed when the cell is subject to heat stress, and is very easy to make - hence it's interest to researchers.

"It is also a very conserved protein so it's pretty much the same in humans and other species," Saibil says.

"GroEL is an interesting one because it is ubiquitous and it really helps proteins to fold. It doesn't just stop them aggregating but seems to actively help proteins to fold in ways which we still don't quite understand.

"Not only that but it makes a container inside which another protein goes and folds. So it's a huge box of protein for other proteins to fold in - it's a piece of machinery that is really quite fascinating."

GroEL works closely with GroES, which makes a lid to cover the open cavity of GroEL's container. "GroEL goes through huge conformational changes, including the binding of the Gro ES lid to make a closed box for protein folding," Saibil says.

"One non-folded protein ends up inside this box and by some mysterious means it gets caught in the hydrophobic binding site. Then when the box forms, all of the pieces of the box twist around so much that the hydrophobic sites get pulled off the non-native protein, and it ends up trapped inside a hydrophilic chamber where there is nothing it can stick to.

"It can't aggregate because it is all by itself and it is confined and can't stretch out in all directions because it is inside a closed container, which is in some cases only a bit bigger than the protein itself. And GroEL manages to make things fold that way - it's quite amazing."

The role of the molecular chaperones in preventing aggregation is hugely important. It was long thought that all the protein needed to fold up into its final three-dimensional shape was the genetic instruction manual. Now, it is known that proteins can get stuck along the way. When proteins start to fold, their hydrophobic parts are sometimes transiently exposed in the process, with those parts showing a liking to stick together and make aggregates.

Aggregates, for reasons still not fully understood, are extremely toxic to the cell and are the basis of many diseases like Alzheimer's and Creutzfeldt-Jakob. "Protein aggregation is something which is extremely damaging and which the cell has invested a huge amount of quality control to stop happening," Saibil says.

"The chaperones are quite a diverse group but one of the most common features is that they prevent aggregates from forming. They generally do that by binding the hydrophobic species and non-native species that are trying to aggregate or ones that are prone to aggregate."