Structure of Key Control Element Behind Protein Misfolding That Can Lead to Disease Identified
Berkeley Lab researchers at the Advanced Light Source have discovered a nucleotide-sensing loop that synchronizes conformational changes in the three domains of group II chaperonin for the proper folding of other proteins.
The gold standard for nanotechnology is nature’s own proteins. These biomolecular nanomachines - macromolecules forged from peptide chains of amino acids - are able to fold themselves into a dazzling multitude of shapes and forms that enable them to carry out an equally dazzling multitude of functions fundamental to life. As important as protein folding is to virtually all biological systems, the mechanisms behind this process have remained a mystery. The fog, however, is being lifted.
A team of researchers with the U.S. Department of Energy (DOE)’s Lawrence Berkeley National Laboratory (Berkeley Lab), using the exceptionally bright and powerful x-ray beams of the Advanced Light Source, have determined the crystal structure of a critical control element within chaperonin, the protein complex responsible for the correct folding of other proteins. The incorrect or “misfolding” of proteins has been linked to many diseases, including Alzheimer’s, Parkinson’s and some forms of cancer.
“We identified, for the first time, a region within group II chaperonins we call the nucleotide-sensing loop, which detects the presence of the ATP molecules that fuel the chaperonin folding motion,” says Paul Adams, a bioengineer with Berkeley Lab’s Physical Biosciences Division and leading authority on x-ray crystallography who led this work. “”We knew that ATP hydrolysis is important for promoting protein folding, but we did not know how ATP activity was sensed and communicated.”