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The folding of a polypeptide is a tug-of-war with bonds within the main chain fighting against interactions between the side chains, according to new results from Marcus F?ndrich (IMB, Jena, Germany) and Christopher Dobson (University of Cambridge, Cambridge, UK). The winner determines whether a polypeptide forms a well-behaved globular structure or the dangerous amyloid fibrils that are associated with diseases such as Alzheimer's or Parkinson's.
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# _- h* x/ W) Q% J! m- oProtein folding depends on specific side–chain interactions, but the new results show that amyloid formation does not. The authors examined polyamino acids (PAAs), peptide repeats of one amino acid that cannot fold into globular structures. Repeats of lysine, glutamine, and other amino acids were, however, able to form fibers with the distinctive cross-? structure of amyloids. "Proteins are defined by the sequence of their side chains," says F?ndrich. "PAAs don't have sequence patterns, but still give rise to amyloids. This means structure isn't defined by the side chains and their interactions, but rather by the main chain." It may also explain why proline insertions, which alter the main chain, perturb amyloid formation.
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Depending on the environment, some PAA side chains were more resistant to amyloid formation than others, however. Charged side chains resisted amyloid formation, probably because they are difficult to align within the densely packed ? sheets. Indeed, the most common repeat associated with amyloid diseases is glutamine, an uncharged amino acid.
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But glutamine is not the only amyloid-forming side chain. Recently, alanine and leucine expansions were also noted in diseases or associated with nuclear fibers. F?ndrich is not surprised. "People said it was the side chains〞that they could interact by hydrogen bonds," he says. "Our data say polylysine and polythreonine work just as well. I imagine this is a more general phenomenon, and we are just realizing how important it is."
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8 w1 T. ?9 O. L' v) Z8 T3 J5 ^5 Z! AReference:
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) o+ w1 C1 k6 WF?ndrich, M., et al. 2002. EMBO J. 21:5682–5690.(Although lacking a specific side–chain p) |
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发表于 2009-3-6 00:14
发表于 
