A gigantic protein complex responsible for looking after bent out of shape proteins has been visualised by scientists working in Japan and the UK.
The structure of the chaperonin complex of the bacteria Thermus thermophilus reveals clues about how the important molecule may do its job of folding new or damaged proteins within cells.
Led by Professor So Iwata of Imperial College London, the team of scientists announce their findings in this month's edition of the journal Structure (August 2004).
The complex comprises three separate parts - two identical 'cage' units lashed back to back, and a 'cap' unit that sits atop the cage, acting as a stopper. The cage contains the unwound, or denatured, protein, while the chaperonin goes about refolding its shape using the cellular energy source, ATP.
The structure of the chaperonin complex is one of the largest and most difficult solved by scientists. Each unit of the cage or cap is made up of seven separate polypeptide chains.
"It's huge," said Professor Iwata. "The cavity can accommodate even very large proteins inside. It makes the perfect environment for the protein to fold."
It is the second structure of a chaperonin complex to be reported by scientists, and is visualised at a resolution of 2.8 Angstroms. The first was published in 1997 by the group of the late Professor Paul Sigler at Yale University, USA.
Unlike the first structure, taken from the chaperonin of gut bacterium Escherichia coli, the Thermus thermophilus structure is a more natural structure revealing the irregular oval interior of the cage's subunits.
Thermus thermophilus is a highly thermophilic bacteria, first found living in deep-sea hot vents. It contains proteins thought to be very similar to those found in the energy powerhouses of plant and animal cells, the mitochondria.
Immediately, the largest users of this new knowledge are biochemists working on the protein and bioinformaticians, searching for similar molecules in other species. Human mitochondria likely use the same type of chaperonin to fold proteins says Professor Iwata. In time their structure may be used in the development of new drugs.
The team believe their structure leads them to an explanation of how the molecule works.
Properly folded proteins tuck away the elements that don't mingle well with water - a property known as hydrophobicity - inside their structure. Denatured proteins with their mis-organised shape allow normally hidden elements to display on the outside, making them appear hydrophobic.
The chaperonin cap recognises the hydrophobicity and 'kicks' the out of shape protein in to the cage for some protein folding therapy.
The folding changes in the cavity are driven by the cell's energy source, ATP. It takes just 10 seconds for a protein to properly fold in the cavity.
The scientists' next goal is to capture these cellular handmaidens in the act of folding strings of denatured protein back together again.
They already have clues as to the sorts of proteins that might be fixed by the chaperonin complex - during their work to crystallise the protein structure they identified 28 separate proteins inside the cage.
"We'd like to be the first to really know what happens, when the protein is enclosed and caught in the act," says Professor Iwata.
In molecular units known as Daltons, the structure of the native chaperonin complex weighs 700 kiloDaltons. It is so big that details of its full structure had to be deposited in two parts to the freely available structure database, Protein Data Bank. It has more than six digits of atomic coordinates, or over a million atoms in the structure mapped and plotted in 3D space.
Professor Iwata is well known for solving the structure of proteins embedded in the membrane of cells, such as the crucial photosynthesis enzyme Photosystem II, published last year in Science. The crystals of chaperonin complex were grown and prepared in Iwata's lab, and after X-ray analysis at the European synchrotron facility, all authors collaboratively solved the structure.