Document Detail


Structural and molecular insights into the mechanism of action of human angiogenin-ALS variants in neurons.
MedLine Citation:
PMID:  23047679     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Mutations in angiogenin (ANG), a member of the ribonuclease A superfamily, are associated with amyotrophic lateral sclerosis (ALS; sporadic and familial) and Parkinson's disease. We have previously shown that ANG is expressed in neurons during neuro-ectodermal differentiation, and that it has both neurotrophic and neuroprotective functions. Here we report the atomic resolution structure of native ANG and 11 ANG-ALS variants. We correlate the structural changes to the effects on neuronal survival and the ability to induce stress granules in neuronal cell lines. ANG-ALS variants that affect the structure of the catalytic site and either decrease or increase the RNase activity affect neuronal survival. Neuronal cell lines expressing the ANG-ALS variants also lack the ability to form stress granules. Our structure-function studies on these ANG-ALS variants are the first to provide insights into the cellular and molecular mechanisms underlying their role in ALS.
Authors:
Nethaji Thiyagarajan; Ross Ferguson; Vasanta Subramanian; K Ravi Acharya
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Nature communications     Volume:  3     ISSN:  2041-1723     ISO Abbreviation:  Nat Commun     Publication Date:  2012  
Date Detail:
Created Date:  2012-10-10     Completed Date:  2013-02-01     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  101528555     Medline TA:  Nat Commun     Country:  England    
Other Details:
Languages:  eng     Pagination:  1121     Citation Subset:  IM    
Affiliation:
Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK.
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MeSH Terms
Descriptor/Qualifier:
Amyotrophic Lateral Sclerosis / genetics,  metabolism*
Animals
Cell Line
Cell Line, Tumor
Crystallography, X-Ray
Cytoplasmic Granules / metabolism*
Humans
Immunohistochemistry
Mice
Mutation
Neurons / metabolism*
Ribonuclease, Pancreatic / chemistry*,  genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
083191//Wellcome Trust; 088464//Wellcome Trust; //Medical Research Council
Chemical
Reg. No./Substance:
EC 3.1.27.-/angiogenin; EC 3.1.27.5/Ribonuclease, Pancreatic
Comments/Corrections

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