Part of the fold
Correct protein folding is essential
When folding goes awry, the results are usually bad. Having the wrong shape may simply mean that a protein does not work properly. Others can lead to accumulated ‘junk’ that eventually kills cells. A new protein has to find the right shape among an astronomical number of possibilities. Some of the intermediate shapes between the unfolded chain and the working protein are ‘stickier’ than the desired end product and begin to clump together before folding is complete.
A famous example is the prion: prion proteins are harmless in their normally folded state but can refold to make a super-stable complex that clogs cells. This switch is irreversible because the diseased form of the prion collects with other prions and induces them to convert to the diseased form too.
Sometimes, as in the fatal Creutzfeldt–Jakob disease (CJD), the defect arises when a prion protein in its normal shape switches to a diseased form inside the patient’s body. But prion disease can also be transmitted between people or even between different species, as discovered when people ate beef products from cows with bovine spongiform encephalopathy (BSE, or ‘mad cow disease’). Starting in the mid-1990s, some people developed what is called variant CJD, thought to be transmitted by prions in the affected meat. In 2011, five deaths in the UK were caused by variant CJD.
Alzheimer’s, Parkinson’s and Huntington’s disease are caused by misfolded proteins that clump together and cannot be disposed of normally. Parkinson’s and Alzheimer’s develop with age, either because the protein clumps grow larger or because the machinery that helps proteins fold properly gets less good at its job.