Abstract
ANGDelMut is a web-based tool for predicting the functional consequences of missense mutations in the angiogenin (ANG) protein, which is associated with amyotrophic lateral sclerosis (ALS). Missense mutations in ANG result in loss of either ribonucleolytic activity or nuclear translocation activity or both of these functions, and in turn cause ALS. However, no web-based tools are available to predict whether a newly identified ANG mutation will possibly lead to ALS. More importantly, no web-implemented method is currently available to predict the mechanisms of loss-of-function(s) of ANG mutants. In light of this observation, we developed the ANGDelMut web-based tool, which predicts whether an ANG mutation is deleterious or benign. The user selects certain attributes from the input panel, which serves as a query to infer whether a mutant will exhibit loss of ribonucleolytic activity or nuclear translocation activity or whether the overall stability will be affected. The output states whether the mutation is deleterious or benign, and if it is deleterious, gives the possible mechanism(s) of loss-of-function. This web-based tool, freely available at http://bioschool.iitd.ernet.in/DelMut/, is the first of its kind to provide a platform for researchers and clinicians, to infer the functional consequences of ANG mutations and correlate their possible association with ALS ahead of experimental findings.
Highlights
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, invariably fatal neurodegenerative disorder that causes the selective destruction of motor neurons, primarily the voluntary muscles
The interface has an information panel that gives a brief overview of the methodology employed in ANGDelMut and the various stages involved in query processing and in analysing and obtaining the output data
In order to understand the predicted functional loss mechanisms of mutants, the user picks certain attributes from the input panel, such as {Conformational switching of His[114], Hydrogen bond interaction path mediated through Leu115 - for loss of ribonucleolytic activity}, {Reduction of solvent-accessible surface area (SASA), Local folding of nuclear localization signal residues 31RRR33 - for loss of nuclear translocation activity} and {RMSD - for stability}, which are analyzed from the simulation trajectory to predict whether a mutation is deleterious or benign
Summary
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, invariably fatal neurodegenerative disorder that causes the selective destruction of motor neurons, primarily the voluntary muscles. ANG binds to its target cells and undergoes nuclear translocation due to the presence of two functional sites such as the receptor-binding site (60NKNGNPHREN68) and the nuclear localization signal (29IMRRRGL35) respectively. Another important function of ANG is the ribonucleolytic activity governed by the catalytic triad residues His[13], Lys[40] and His1148,9. Several reports on laboratory-based functional assay experiments[9,10,11,12] and molecular dynamics (MD) simulations[6,7,13] have shown that loss of either ribonucleolytic activity or nuclear translocation activity or both of these functions due to missense mutations in ANG cause ALS. In light of these observations, we developed and hosted the ANGDelMut web-based tool, available at http://bioschool.iitd.ernet.in/DelMut/, which utilizes a MD simulation-based protocol to capture certain structural and dynamic features of simulated mutant proteins to predict mechanisms of functional loss
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