Trends in Biochemical Sciences
FrontlinesProtein misfolding, evolution and disease
Section snippets
Protein misfolding is linked to disease
Despite these controls, a range of debilitating human diseases is associated with protein misfolding events that result in the malfunctioning of the cellular machinery5. Cystic fibrosis is one example where mutations in the gene encoding a crucial transport protein result in the protein folding incorrectly and hence not being secreted in the quantity required for proper function. Other diseases, including some types of familial emphysema, result from mutations that result in improper
Soluble proteins convert into aggregates under denaturing conditions
Studies of the mechanism of the conversion of the normally soluble proteins into amyloid fibrils have benefited from the fact that, in many cases, the structural transitions of the disease-associated molecules can be reproduced under laboratory conditions7. In order to achieve this, a common procedure has been to expose the folded proteins to mildly denaturing conditions, such as low pH or elevated temperatures. Those transitions that have been studied in detail have generally revealed the
Amyloid is a generic structural form of proteins
The involvement of only a handful of proteins in amyloid diseases has commonly been thought to be associated with some particular conformational character of the protein sequences involved. But recently compelling evidence has accumulated that the ability to form amyloid is not a peculiarity of this small group of proteins. A clue came, fortuitously, from an NMR study of the SH3 module of PI3 kinase, which has no connection with any known disease19. At low pH, where the protein is at least
Living systems avoid forming amyloid
If amyloid fibril formation is a generic property of polypeptide chains, why is its occurrence in biology restricted to a very small number of proteins? What prevents the rest of our proteins forming this material in our bodies? And why are aggregates normally seen only when the usual amino-acid sequence of the disease-related proteins is altered by mutation, or following infection, or in old age? These questions are particularly pertinent because, once formed, amyloid fibrils are essentially
New insights into evolutionary biology?
The conventional view of protein structures is that they have emerged under the pressure of the development of greater efficiency and new functionalities. Properties such as the cooperativity of their structures ensure that a single, well-defined structure exists in solution to allow efficient binding to other molecules and effective functional behaviour, for example, catalysis of very specific chemical reactions. It is interesting to speculate that avoidance of aggregation, particularly to
Acknowledgements
I acknowledge very valuable discussions on this article with John Ellis and Carol Robinson. I am grateful to Jose Jiminez and Helen Saibil for providing Figure 3 and to Adam Rostom for producing Figure 1. This paper is a contribution from the Oxford Centre for Molecular Sciences, which is funded by the BBSRC, EPSRC and MRC. The research of C. M. D. is also supported by the Howard Hughes Medical Institute and the Wellcome Trust.
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