ANGDelMut – a web-based tool for predicting and analyzing functional loss mechanisms of deleterious angiogenin mutations causing amyotrophic lateral sclerosis

Suhas V Vasaikar,James Gomes,Bhyravabhotla Jayaram,Aditya K Padhi

doi:10.12688/f1000research.2-227.v1

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, there are no web-based tools available to predict whether a newly identified ANG mutation will be ALS causative. More importantly, no web-implemented method is currently available to elucidate 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 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 their 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
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 molecular dynamics (MD) simulation-based protocol to capture certain structural and dynamic features of simulated mutant proteins to predict mechanisms of functional loss
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

Summary

Introduction

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 receptorbinding 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 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

Methods

Results

Conclusion