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.
- amyotrophic lateral sclerosis
- stress granules
- ALS mutants
- crystal structure
Thiyagarajan, N., Ferguson, R., Subramanian, V., & Acharya, K. R. (2012). Structural and molecular insights into the mechanism of action of human angiogenin-ALS variants in neurons. Nature Communications, 3, . https://doi.org/10.1038/ncomms2126