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  Vol 426 No 6968 (Insight) pp883-909

18/25 December 2003

  introduction
  review articles
  progress

protein misfolding

ADAM SMITH
Adam Smith Editor, Nature Reviews Drug Discovery

At school it all sounded so simple — transcription turns DNA into RNA, and translation of RNA gives you protein. But the often forgotten third step in this process, the folding of the translated linear strand of amino acids into a fully functional three-dimensional protein, is one of the most complex challenges facing the cellular protein factory.

Although it has long been known that the amino-acid sequence in some way dictates the biologically active conformation of a protein, the experimental tools required to probe the intermediate states along the folding pathway have only begun to become available in the past decade or so. These tools are revealing a tightly regulated assembly line, where multiple factors guide nascent proteins to select the correct shape from an almost infinite array of possibilities.

Becoming apparent are the stringent quality-control systems that come into play if the folding process fails, ensuring that the misfolded products are targeted for degradation before they cause harm. Those that escape this cellular surveillance are prone to forming aggregates that can damage or kill cells through mechanisms that are just beginning to be understood.

A huge variety of previously unrelated diseases, such as prion diseases, diabetes and cancer, share the pathological feature of aggregated misfolded protein deposits. This suggests the exciting possibility that these 'protein-misfolding diseases' are linked by common principles, and may therefore present common targets for therapeutic intervention.

The articles in this Insight give an interdisciplinary overview of the field of protein-folding research, treading a path from protein chemistry through cell biology to misfolding diseases and the potential for therapeutic development.

This Insight is entirely self-contained; however, its scope and focus were mirrored in the organization of last year's Horizon Symposium on 'Protein Folding and Disease', the first in a new series of discussion meetings created as a joint initiative by Nature Publishing Group and Aventis. Complementary material can therefore be found at http://www.horizonsymposia.com.

 introduction
  protein misfolding 883
ADAM SMITH
doi:10.1038/426883a
Full text | PDF (484k)
 review articles
  Protein folding and misfolding 884
CHRISTOPHER M. DOBSON
doi:10.1038/nature02261
Summary | Full text | PDF (448k)
 progress
  Quality control in the endoplasmic reticulum protein factory 891
ROBERTO SITIA AND INEKE BRAAKMAN
doi:10.1038/nature02262
Summary | Full text | PDF (239k)
 review articles
  Protein degradation and protection against misfolded or damaged proteins 895
ALFRED L. GOLDBERG
doi:10.1038/nature02263
Summary | Full text | PDF (195k)
  Folding proteins in fatal ways 900
DENNIS J. SELKOE
doi:10.1038/nature02264
Summary | Full text | PDF (216k)
  Therapeutic approaches to protein-misfolding diseases 905
FRED E. COHEN AND JEFFERY W. KELLY
doi:10.1038/nature02265
Summary | Full text | PDF (238k)
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