Fast prediction of deleterious angiogenin mutations causing amyotrophic lateral sclerosis

Padhi, Aditya K.; Vasaikar, Suhas; Jayaram, B.; Gomes, James

doi:10.1016/j.febslet.2013.04.022

Cited by 15 publications

(19 citation statements)

References 30 publications

(112 reference statements)

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“…Since its first discovery by Greenway et al 5 , the ANG gene has emerged as one of the most frequently mutated genes found in ALS patients of diverse ethnic groups. A total of 19 missense mutations in ANG have been associated with ALS 6, 7 . In addition, several rare mutations have also been discovered in the ANG gene; however, it is not yet known whether these are instrumental in causing ALS 7 .…”

Section: Introductionmentioning

confidence: 99%

“…A total of 19 missense mutations in ANG have been associated with ALS 6, 7 . In addition, several rare mutations have also been discovered in the ANG gene; however, it is not yet known whether these are instrumental in causing ALS 7 . The human ANG gene encodes a 14.1 kDa long monomeric ANG protein that induces neovascularization, maintains the physiology and health of motor neurons by inducing angiogenesis, stimulates neurite outgrowth and path-finding and protects motor neurons from hypoxia-induced death and hence acts as a neuroprotective factor 8– 12 .…”

Section: Introductionmentioning

confidence: 99%

“…Another important function of ANG is the ribonucleolytic activity governed by the catalytic triad residues His13, Lys40 and His114 8, 9 . Several reports on laboratory-based functional assay experiments 9– 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. However, no web-based tool is currently available that can establish the functional consequences of ANG mutations and predict the loss-of-function(s) mechanisms.…”

Section: Introductionmentioning

confidence: 99%

“…The method implemented in ANGDelMut has been previously tried and tested, and in addition, the functional loss predictions of mutants have been correlated with known experimental reports 6, 7, 13 . When a user submits a mutation, the mutant protein is prepared in silico by replacing the target residue with the desired amino acid residue.…”

Section: Introductionmentioning

confidence: 99%

“…Subsequently, a standard MD simulation-based protocol is followed based on certain optimized parameters, which performs extensive MD simulations for 25 ns. The simulated trajectories are then visualized and analyzed for the presence of certain global attributes 6, 7, 13 , which in turn indicate whether a mutant will probably exhibit any loss-of-function(s). The output of ANGDelMut suggests the nature of the mutation; it’s probable association with ALS, and further highlights the plausible molecular mechanisms of loss-of-functions to the user ( Figure 1).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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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.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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Angiogenin mutations in Hungarian patients with amyotrophic lateral sclerosis: Clinical, genetic, computational, and functional analyses

et al. 2019

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Introduction Mutations in the angiogenin ( ANG ) gene are known to be associated with both familial and sporadic amyotrophic lateral sclerosis (ALS). The majority of disease‐causing mutations of ANG result in loss of either ribonucleolytic activity, nuclear translocation activity or both. Methods We sequenced ANG gene from a total of 136 sporadic ALS patients and 112 healthy controls of Hungarian origin. To elucidate the role of the R33W mutation in the disease mechanism, computational, and functional analyses were performed. Results Mutation screening revealed a mutation located in the signal peptide (M‐24I) and two mutations that affect the mature protein (R33W, V103I). The R33W mutation, which has not been previously detected in ALS patients, affects the key amino acid of the nuclear translocation signal of the ANG protein. Molecular dynamics simulations suggested that the R33W mutation results in partial loss of ribonucleolytic activity and reduced nuclear translocation activity. The ribonucleolytic assay and nuclear translocation assay of the R33W ANG protein confirmed the molecular dynamics results. Conclusions In the Hungarian ALS population, the observed frequency of ANG mutations was 2.9%, which is higher than previously reported for sporadic cohorts. The evidence from computational and functional analyses support the deleterious effect of the novel R33W variant detected in this study.

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Insights into the role of d‐amino acid oxidase mutations in amyotrophic lateral sclerosis

Padhi

Hazra

2018

J of Cellular Biochemistry

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Missense mutations in the coding region of d-amino acid oxidase (DAO) have been found in patients suffering from amyotrophic lateral sclerosis (ALS). Mutations primarily impair the enzymatic activity of DAO and cause neurodegeneration due to an abnormal accumulation of d-serine in the spinal cord. However, the structural and dynamic changes that lead to impaired enzymatic activity are not fully understood. We present here extensive molecular dynamics simulations of wild-type, and all reported ALS-associated DAO mutants to elucidate the plausible mechanisms of impaired enzymatic activity, a critical function needed for neuroprotection. Simulation results show that DAO mutations disrupt several key interactions with the active site residues and decrease the conformational flexibility of active site loop comprising 216 to 228 residues, necessary for substrate binding and product release. This conformational restriction of the active site loop in the mutants is mainly due to the distortion of critical salt bridge and hydrogen bond interactions compared with wild-type. Furthermore, binding free energy calculations show that DAO mutants have a lower binding affinity toward cofactor flavin adenine dinucleotide and substrate imino-serine than the wild-type. A closer look at the cofactor and substrate interaction profiles further show that DAO mutants have lost several critical interactions with the neighboring residues as compared with wild-type. Taken together, this study provides first-hand explanation of crucial structural features that lead to the loss of enzymatic function in DAO mutants and highlights the need of further genomic scans of patients with ALS to map the association of novel DAO variants in ALS pathophysiology.

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Fast prediction of deleterious angiogenin mutations causing amyotrophic lateral sclerosis

Cited by 15 publications

References 30 publications

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

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

Angiogenin mutations in Hungarian patients with amyotrophic lateral sclerosis: Clinical, genetic, computational, and functional analyses

Insights into the role of d‐amino acid oxidase mutations in amyotrophic lateral sclerosis

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