Protein folding aficionados may well want to hold on to their December 18/25 copy of Nature, which devotes a special insight section to the topic. Five separate reviews summarize the research and present thinking on everything from protein synthesis to extracellular amyloids.

Starting at the beginning—protein synthesis—Chris Dobson (University of Cambridge, U.K.) reviews how primary amino acid sequence and the cellular environment contribute to the folding of a nascent protein. Dobson elaborates on how the folding/misfolding process can be used to regulate cellular processes and the chemistry behind potentially lethal misfolding events such as amyloid aggregation. Roberto Sitia (Universita Vita-Salute San Raffaele, Milano, Italy) and Ineke Braakman (Utrecht University, The Netherlands) go on to review the quality control mechanisms in the endoplasmic reticulum (ER) that govern the maturation of proteins destined for export. Sitia and Braakman emphasize how the crowded environment of the ER can lead to folding errors, and how essential are the roles played by chaperones and signaling molecules, which have come under close scrutiny as potential drug targets. Alfred Goldberg (Harvard Medical School) describes how the proteasome keeps the cell relatively free of misfolded proteins, and emphasizes environmental conditions that can affect the proteasome, such as heat shock and oxidative stress. He also discusses how misfolded proteins may be recognized by the proteolytic machinery. Dennis Selkoe (Brigham and Women's Hospital, Boston) addresses how aggregates of misfolded proteins—particularly amyloids—can be fatal, whether they accumulate inside or outside the cell. In particular, Selkoe discusses the susceptibility of postmitotic neurons, which can be inundated with more than their fair share of misfolded proteins. And last, but by no means least, Fred Cohen (University of California, San Francisco) and Jeffrey Kelly (The Scripps Research Institute, La Jolla, California) discuss therapeutic approaches to protein-folding diseases, including the use of small ligands to stabilize the native state of proteins susceptible to misfolding.—Tom Fagan


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Primary Papers

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