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Metabolic Brain Disease

, Volume 34, Issue 6, pp 1661–1677 | Cite as

Rare Angiogenin and Ribonuclease 4 variants associated with amyotrophic lateral sclerosis exhibit loss-of-function: a comprehensive in silico study

  • Aditya K. PadhiEmail author
  • Priyam Narain
  • James GomesEmail author
Original Article

Abstract

Amyotrophic Lateral Sclerosis (ALS), a debilitating neurodegenerative disorder is related to mutations in a number of genes, and certain genes of the Ribonuclease (RNASE) superfamily trigger ALS more frequently. Even though missense mutations in Angiogenin (ANG) and Ribonuclease 4 (RNASE4) have been previously shown to cause ALS through loss-of-function mechanisms, understanding the role of rare variants with a plausible explanation of their functional loss mechanisms is an important mission. The study aims to understand if any of the rare ANG and RNASE4 variants catalogued in Project MinE consortium caused ALS due to loss of ribonucleolytic or nuclear translocation or both these activities. Several in silico analyses in combination with extensive molecular dynamics (MD) simulations were performed on wild-type ANG and RNASE4, along with six rare variants (T11S-ANG, R122H-ANG, D2E-RNASE4, N26K-RNASE4, T79A-RNASE4 and G119S-RNASE4) to study the structural and dynamic changes in the catalytic triad and nuclear localization signal residues responsible for ribonucleolytic and nuclear translocation activities respectively. Our comprehensive analyses comprising 1.2 μs simulations with a focus on physicochemical, structural and dynamic properties reveal that T11S-ANG, N26K-RNASE4 and T79A-RNASE4 variants would result in loss of ribonucleolytic activity due to conformational switching of catalytic His114 and His116 respectively but none of the variants would lose their nuclear translocation activity. Our study not only highlights the importance of rare variants but also demonstrates that elucidating the structure-function relationship of mutant effectors is crucial to gain insights into ALS pathophysiology and in developing effective therapeutics.

Keywords

Amyotrophic lateral sclerosis Angiogenin Loss-of-functions Molecular dynamics Physicochemical properties Rare variants Ribonuclease 4 

Notes

Acknowledgements

Aditya K. Padhi acknowledges Council of Scientific and Industrial Research (CSIR), Government of India for research fellowship. Priyam Narain is thankful to IIT Delhi for Senior Research Fellowship. Helpful suggestions from Prof B. Jayaram (IIT Delhi) are gratefully acknowledged.

Author’s contributions

AKP; Collection of variants: PN; Analyzed the data: AKP, PN and JG; Contributed to the writing of the manuscript: AKP, PN and JG.

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

Research involving in human and animal rights

This article does not contain any study with human or animal subjects performed by any of the authors.

Supplementary material

11011_2019_473_MOESM1_ESM.pdf (552 kb)
ESM 1 (PDF 551 kb)

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Authors and Affiliations

  1. 1.Kusuma School of Biological SciencesIndian Institute of Technology DelhiNew DelhiIndia
  2. 2.Laboratory for Structural Bioinformatics, Field for Structural Molecular Biology, Centre for Biosystems Dynamics ResearchRIKENYokohamaJapan

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