title: Protein aggregation due to nsSNP resulting in P56S VABP protein is associated with amyotrophic lateral sclerosis.
abstract: 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.
authors.affiliation: School of Biosciences and Technology, VIT University, Vellore 632014, Tamil Nadu, India.
authors.forename: Chundi
authors.initials: C
authors.lastname: Vinay Kumar
authors.affiliation: School of Biosciences and Technology, VIT University, Vellore 632014, Tamil Nadu, India.
authors.forename: K M
authors.initials: KM
authors.lastname: Kumar
authors.affiliation: School of Biosciences and Technology, VIT University, Vellore 632014, Tamil Nadu, India.
authors.forename: Rayapadi
authors.initials: R
authors.lastname: Swetha
authors.affiliation: School of Biosciences and Technology, VIT University, Vellore 632014, Tamil Nadu, India.
authors.forename: Sudha
authors.initials: S
authors.lastname: Ramaiah
authors.affiliation: School of Biosciences and Technology, VIT University, Vellore 632014, Tamil Nadu, India. Electronic address: aanand@vit.ac.in.
authors.forename: Anand
authors.initials: A
authors.lastname: Anbarasu
mesh_terms: D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism; D066264:Datasets as Topic; D006801:Humans; D051605:Kv Channel-Interacting Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D066263:Protein Aggregation, Pathological / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000235:genetics
chemical_list: C496750:KCNIP1 protein, human; D051605:Kv Channel-Interacting Proteins
keywords: ALS; Molecular dynamics simulation; SNP analysis; VAPB protein