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Nat Commun. 2012;3:1121. doi: 10.1038/ncomms2126.

Structural and molecular insights into the mechanism of action of human angiogenin-ALS variants in neurons.

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  • 1Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK.

Abstract

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.

PMID:
23047679
[PubMed - indexed for MEDLINE]
PMCID:
PMC3493651
Free PMC Article
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