Computational and functional characterization of Angiogenin mutations, and correlation with amyotrophic lateral sclerosis.
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Padhi AK, Banerjee K, Gomes J, Banerjee M
Computational and functional characterization of Angiogenin mutations, and correlation with amyotrophic lateral sclerosis.
PLoS One. 2014 Nov 5;9(11):e111963. doi: 10.1371/journal.pone.0111963. eCollection 2014.
- PubMed ID
- 25372031 [ View in PubMed]
- Abstract
The Angiogenin (ANG) gene is frequently mutated in patients suffering from the neurodegenerative disease--amyotrophic lateral sclerosis (ALS). Most of the ALS-causing mutations in Angiogenin affect either its ribonucleolytic or nuclear translocation activity. Here we report the functional characterization of two previously uncharacterized missense mutations in Angiogenin--D22G and L35P. We predict the nature of loss-of-function(s) in these mutants through our previously established Molecular Dynamics (MD) simulation extended to 100 ns, and show that the predictions are entirely validated through biochemical studies with wild-type and mutated proteins. Based on our studies, we provide a biological explanation for the loss-of-function of D22G-Angiogenin leading to ALS, and suggest that the L35P-Angiogenin mutation would probably cause ALS symptoms in individuals harboring this mutation. Our study thus highlights the strength of MD simulation-based predictions, and suggests that this method can be used for correlating mutations in Angiogenin or other effector proteins with ALS symptoms.