Chaperones, explains Horwich, are proteins that have hydrophobic surfaces that recognise and bind to the exposed hydrophobic surfaces of improperly folded proteins. "This prevents non-native [misfolded] protein molecules making wrongful interactions with other molecules of the same sort", a process that could cause aggregation, says Horwich. "Small proteins probably don't normally need chaperones to fold, but large complex proteins need kinetic assistance. And once mutation enters the scene, the ability of any protein to reach its native, active state is strongly affected."How do misfolded proteins cause disease? The easiest situation to explain is exemplified by cystic fibrosis, in which misfolding leads to the loss of function of a critical ion channel. Similarly, in a1-antitrypsin deficiency, loss of function due to misfolding decreases the enzyme's ability to protect the lung, which can lead to emphysema. However, misfolding also causes a1-antitrypsin to build up within hepatocytes and causes inclusions to form that can lead to cell death, hepatitis, and fibrosis. Because the misfolded protein has a new characteristic--the ability to form inclusions--researchers describe this as a "gain of function". Other disorders where there is "gain of function" include Huntington's, Alzheimer's, and Parkinson's disease. Might it be possible to correct these diseases by persuading the misfolded protein to fold correctly?William Welch (University of California San Francisco, CA, USA) was one of the first people to try to find a way to correct protein misfolding. "My lab was working on the heat shock response and we were intrigued by the observation that CFTR?F508, the commonest cystic fibrosis mutation, produced a protein that was temperature sensitive for folding." This means that at normal cellular temperatures, the cystic fibrosis transmembrane conductance regulator (CFTR) misfolds and doesn't make it to the cell surface where its activity is needed.
