Protein aggregation due to nsSNP resulting in P56S VABP protein is associated with amyotrophic lateral sclerosis

• Published in: Journal of theoretical biology 2014-08, Vol.354, p.72-80
• Main Authors: Vinay Kumar, Chundi, Kumar, K.M., Swetha, Rayapadi, Ramaiah, Sudha, Anbarasu, Anand
• Format: Article
• Language: English
• Subjects: ALS; Amino Acid Substitution; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Datasets as Topic; Humans; Kv Channel-Interacting Proteins - chemistry; Kv Channel-Interacting Proteins - genetics; Kv Channel-Interacting Proteins - metabolism; Molecular Dynamics Simulation; Mutation, Missense; Polymorphism, Single Nucleotide; Protein Aggregation, Pathological - genetics; Protein Aggregation, Pathological - metabolism; SNP analysis; Unfolded Protein Response - genetics; VAPB protein
• ISSN: 0022-5193; 1095-8541
• DOI: 10.1016/j.jtbi.2014.03.027

Mutations in the gene encoding vesicle-associated membrane protein (VAPB) cause amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. The VAPB gene is mapped to chromosome number 20 and can be found at cytogenetic location 20q13.33 of the chromosome. VAPB is seen to play a significant role in the unfolded protein response (UPR), which is a process that suppresses the accumulation of unfolded proteins in the endoplasmic reticulum. Earlier studies have reported two points; which we have analyzed in our study. Firstly, the mutation P56S in the VAPB is seen to increase the stability of the protein and secondly, the mutation P56S in VAPB is seen to interrupt the functioning of the gene and loses its ability to be involved in the activation of the IRE1/XBP1 pathway which leads to ALS. With correlation on the previous research studies on the stability of this protein, we carried out Molecular dynamics (MD) simulation. We analyzed the SNP results of 17 nsSNPs obtained from dbSNP using SIFT, polyphen, I-Mutant, SNP&GO, PhDSNP and Mutpred to predict the role of nsSNPs in VAPB. MD simulation is carried out and plots for RMSD, RMSF, Rg, SASA, H-bond and PCA are obtained to check and prove the stability of the wild type and the mutant protein structure. The protein is checked for its aggregation and the results obtained show changes in the protein structure that might result in the loss of function. •Computationally predicted deleterious nsSNP P56S in VAPB might cause ALS.•Molecular dynamics simulation increases the computational prediction accuracy of the disease associated SNPs.•There is both structural and functional impact of P56S on VABP protein.•Secondary structure prediction indicates protein aggregation.