Document Detail


Strategies for stabilizing superoxide dismutase (SOD1), the protein destabilized in the most common form of familial amyotrophic lateral sclerosis.
MedLine Citation:
PMID:  21098299     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Amyotrophic lateral sclerosis (ALS) is a disorder characterized by the death of both upper and lower motor neurons and by 3- to 5-yr median survival postdiagnosis. The only US Food and Drug Administration-approved drug for the treatment of ALS, Riluzole, has at best, moderate effect on patient survival and quality of life; therefore innovative approaches are needed to combat neurodegenerative disease. Some familial forms of ALS (fALS) have been linked to mutations in the Cu/Zn superoxide dismutase (SOD1). The dominant inheritance of mutant SOD1 and lack of symptoms in knockout mice suggest a "gain of toxic function" as opposed to a loss of function. A prevailing hypothesis for the mechanism of the toxicity of fALS-SOD1 variants, or the gain of toxic function, involves dimer destabilization and dissociation as an early step in SOD1 aggregation. Therefore, stabilizing the SOD1 dimer, thus preventing aggregation, is a potential therapeutic strategy. Here, we report a strategy in which we chemically cross-link the SOD1 dimer using two adjacent cysteine residues on each respective monomer (Cys111). Stabilization, measured as an increase in melting temperature, of ∼20 °C and ∼45 °C was observed for two mutants, G93A and G85R, respectively. This stabilization is the largest for SOD1, and to the best of our knowledge, for any disease-related protein. In addition, chemical cross-linking conferred activity upon G85R, an otherwise inactive mutant. These results demonstrate that targeting these cysteine residues is an important new strategy for development of ALS therapies.
Authors:
Jared R Auclair; Kristin J Boggio; Gregory A Petsko; Dagmar Ringe; Jeffrey N Agar
Related Documents :
8824299 - Mechanism of topoisomerase ii inhibition by staurosporine and other protein kinase inhi...
21719299 - Synthesis and biological activity of naphthyl-substituted (b-ring) benzophenone derivat...
9519409 - Structure of escherichia coli ribokinase in complex with ribose and dinucleotide determ...
21098299 - Strategies for stabilizing superoxide dismutase (sod1), the protein destabilized in the...
20124709 - A conserved mechanism of autoinhibition for the ampk kinase domain: atp-binding site an...
8451239 - Crystal structures of two mutants of adenylate kinase from escherichia coli that modify...
24900739 - Contribution of cage-shaped structure of physalins to their mode of action in inhibitio...
22286559 - Synthesis of n-substituted ε-hexonolactams as pharmacological chaperones for the treatm...
19199229 - Eremophilane-type sesquiterpene derivatives from ligularia hodgsonii.
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-11-22
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  107     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2011-03-22     Completed Date:  2011-05-12     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  21394-9     Citation Subset:  IM    
Affiliation:
Department of Chemistry and Rosenstiel Basic Medical Sciences Research Center, Brandeis University, 415 South Street, Waltham, MA 02454, USA.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Amyotrophic Lateral Sclerosis / enzymology*,  genetics
Animals
Cross-Linking Reagents / chemistry
Disulfides / chemistry
Enzyme Stability*
Humans
Maleimides / chemistry
Mice
Molecular Structure
Mutation
Protein Multimerization
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Sulfhydryl Compounds / chemistry
Superoxide Dismutase / chemistry,  genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
1R21NS071256/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Cross-Linking Reagents; 0/Disulfides; 0/Maleimides; 0/Sulfhydryl Compounds; 541-59-3/maleimide; EC 1.15.1.-/superoxide dismutase 1; EC 1.15.1.1/Superoxide Dismutase
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Dry amyloid fibril assembly in a yeast prion peptide is mediated by long-lived structures containing...
Next Document:  Time-dependent electron phenomena at surfaces.