r she nor other scientists studying protein folding claim that this quest will be easy.Since the 1950s, scientists have known that the information necessary for a protein to fold properly is encoded in its aminoacid sequence. However, in the past 15 years, researchers have discovered that matters are not quite that simple within cells. "In 1987, we were studying how proteins got into mitochondria", says Arthur Horwich (Yale University School of Medicine, New Haven, CT, USA). "It was becoming clear that for this to happen, proteins had to unfold so that they could get through the mitochondrial membranes rather like a strand of spaghetti. The question we and others asked was 'Do proteins spontaneously refold once they get into mitochondria or is some sort of machine needed?'"Cells were soon discovered to have several such machines--called chaperones--that assist protein folding particularly when cells are exposed to stresses such as heat. 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

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