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

Nethaji Thiyagarajan, Ross Ferguson, Vasanta Subramanian () and K. Ravi Acharya ()
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Nethaji Thiyagarajan: University of Bath, Claverton Down
Ross Ferguson: University of Bath, Claverton Down
Vasanta Subramanian: University of Bath, Claverton Down
K. Ravi Acharya: University of Bath, Claverton Down

Nature Communications, 2012, vol. 3, issue 1, 1-14

Abstract: 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.

Date: 2012
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DOI: 10.1038/ncomms2126

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