|
 |
|
|
| Subject Categories: Proteins | Molecular Biology of Disease |
|
| The EMBO Journal
(2007) 26, 855–866, doi:10.1038/sj.emboj.7601528 Published online 25 January 2007 |
|
| Impaired post-translational folding of familial ALS-linked Cu, Zn superoxide dismutase mutants |
|
|
| Cami K Bruns and Ron R Kopito |
|
|
Department of Biological Sciences, Stanford University, Stanford, CA, USA To whom correspondence should be addressed Ron R Kopito, Department of Biological Sciences, Stanford University, Stanford, CA 94305-5020, USA. Tel.: +1 650 723 7581; Fax: +1 650 724 9975; E-mail: kopito@stanford.edu Received 20 October 2006; Accepted 5 December 2006; Published online 25 January 2007. |
|
|
|
| Abstract |
|
| Over 110 structurally diverse missense mutations in the superoxide dismutase (SOD1) gene have been linked to the pathogenesis of familial amyotrophic lateral sclerosis (FALS), yet the mechanism by which these lead to cytotoxicity still remains unknown. We have synthesized wild-type and mutant SOD1 in synchronized cell-free reticulocyte extracts replete with the full complement of molecular chaperones and folding facilitators that are normally required to fold this metalloenzyme. Here, we report that, despite being a small, single-domain protein, human SOD1 folds post-translationally to a hyperstable native-like conformation without a requirement for ATP-dependent molecular chaperones. SOD1 folding requires tight Zn but not Cu binding and proceeds through at least three kinetically and biochemically distinct states. We find that all 11 FALS-associated SOD1 mutants examined using this system delay the kinetics of folding, but do not necessarily preclude the formation of native-like states. These data suggest a model whereby impaired post-translational folding increases the population of on- and off-pathway folding intermediates that could provide an important source of proto-toxic protein, and suggest a unifying mechanism for SOD1-linked FALS pathogenesis. |
|
| Keywords: Amyotrophic lateral sclerosis, cell-free protein synthesis, protein folding, superoxide dismutase |
|
|
|
Top of page MORE ARTICLES LIKE THISThese links to content published by NPG are automatically generated NEWS AND VIEWSOxidation versus aggregation ? how do SOD1 mutants cause ALS? Nature Medicine News and Views (01 Dec 2000) RESEARCHJournal of Investigative Dermatology Original Article Mutant SOD1 causes motor neuron disease independent of copper chaperone?mediated copper loading Nature Neuroscience Article (01 Apr 2002) Oxygen-induced maturation of SOD1: a key role for disulfide formation by the copper chaperone CCS The EMBO Journal Article (21 Jul 2004) |
|
|
| |
| |
| |
 | Email link to a friend |
| |
 | Download PDF |
| |
 | Full text |
| |
| |
| |
 | Next article |
| |
 | Previous article |
| |
 | Table of contents |
| |
| |
 | Rights and permissions |
| |
 | Reprints |
| |
| |
| |
 Register for table of contents by email | |
| |
| |
| |
