Computational and functional characterization of Angiogenin mutations, and correlation with amyotrophic lateral sclerosis.
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.
Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, New Delhi, India.
Aditya K
AK
Padhi
Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, New Delhi, India.
Kamalika
K
Banerjee
Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, New Delhi, India.
James
J
Gomes
Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, New Delhi, India.
Manidipa
M
Banerjee
D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D020125:Mutation, Missense; D017434:Protein Structure, Tertiary; D012259:Ribonuclease, Pancreatic / Q000737:chemistry* / Q000235:genetics*
C046366:angiogenin; D012259:Ribonuclease, Pancreatic