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In silico analysis predicting effects of deleterious SNPs of human RASSF5 gene on its structure and functions.

ABSTRACT: Ras association domain-containing protein 5 (RASSF5), one of the prospective biomarkers for tumors, generally plays a crucial role as a tumor suppressor. As deleterious effects can result from functional differences through SNPs, we sought to analyze the most deleterious SNPs of RASSF5 as well as predict the structural changes associated with the mutants that hamper the normal protein-protein interactions. We adopted both sequence and structure based approaches to analyze the SNPs of RASSF5 protein. We also analyzed the putative post translational modification sites as well as the altered protein-protein interactions that encompass various cascades of signals. Out of all the SNPs obtained from the NCBI database, only 25 were considered as highly deleterious by six in silico SNP prediction tools. Among them, upon analyzing the effect of these nsSNPs on the stability of the protein, we found 17 SNPs that decrease the stability. Significant deviation in the energy minimization score was observed in P350R, F321L, and R277W. Besides this, docking analysis confirmed that P350R, A319V, F321L, and R277W reduce the binding affinity of the protein with H-Ras, where P350R shows the most remarkable deviation. Protein-protein interaction analysis revealed that RASSF5 acts as a hub connecting two clusters consisting of 18 proteins and alteration in the RASSF5 may lead to disassociation of several signal cascades. Thus, based on these analyses, our study suggests that the reported functional SNPs may serve as potential targets for different proteomic studies, diagnosis and therapeutic interventions.

SUBMITTER: Hossain MS

PROVIDER: S-EPMC7471297 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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In silico analysis predicting effects of deleterious SNPs of human RASSF5 gene on its structure and functions.

Hossain Md Shahadat MS Roy Arpita Singha AS Islam Md Sajedul MS

Scientific reports 20200903 1

Ras association domain-containing protein 5 (RASSF5), one of the prospective biomarkers for tumors, generally plays a crucial role as a tumor suppressor. As deleterious effects can result from functional differences through SNPs, we sought to analyze the most deleterious SNPs of RASSF5 as well as predict the structural changes associated with the mutants that hamper the normal protein-protein interactions. We adopted both sequence and structure based approaches to analyze the SNPs of RASSF5 prot ...[more]

PMID: 32884013

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Project description:BackgroundTuftelin 1 (TUFT1) gene is important in the development and mineralization of dental enamel. The study aimed to identify potential functionally deleterious non-synonymous SNPs (nsSNPs) in the TUFT1 gene by using different in silico tools. The deleterious missense SNPs were identified from SIFT, PolyPhen-2, PROVEAN, SNPs & GO, PANTHER, and SNAP2. The stabilization, conservation, and three-dimensional modeling of mutant proteins were analyzed by I-Mutant 3.0, Consurf, and Project HOPE, respectively. The protein-protein interaction using STRING, GeneMANIA for gene-gene interaction, and DynaMut for evaluating the impact of the mutation on protein stability, conformation, and flexibility.ResultsEight deleterious nsSNPs (E242A, R303W, K182N, K123N, R117W, H289Q, R203W, and Q107R) out of 304 were found to have high-risk damaging effects using six in silico tools. Among them, K182N and K123N alone had increased stability, whereas E242A, R303W, R117W, H289Q, Q107R, and R203W exhibited a decrease in protein stability, based on DDG values. Meanwhile, all the eight deleterious nsSNPs altered the size, charge, hydrophobicity, and spatial organization of the amino acids and predominantly had alpha helix domains. These deleterious variants were located in highly conserved regions except R203W. Protein-protein interaction predicted that TUFT1 interacted with ten proteins that are involved in enamel mineralization and odontogenesis. Gene-gene interaction network showed that TUFT1 is involved in physical interactions, gene co-localization, and pathway interactions. DynaMut ΔΔG values predicted that five nsSNPs were destabilizing the protein, ΔΔG ENCoM values showed a destabilizing effect for all mutants, and seven nsSNPs increased the molecular flexibility of TUFT1.ConclusionOur study predicted eight functional SNPs that had detrimental effects on the structure and function of the TUFT1 gene. This will aid in the development of candidate deleterious markers as a potential target for disease diagnosis and therapeutic interventions.

Project description:Hennekam lymphangiectasia-lymphedema syndrome has been linked to single-nucleotide polymorphisms in the CCBE1 (collagen and calcium-binding EGF domains 1) gene. Several bioinformatics methods were used to find the most dangerous nsSNPs that could affect CCBE1 structure and function. Using state-of-the-art in silico tools, this study examined the most pathogenic nonsynonymous single-nucleotide polymorphisms (nsSNPs) that disrupt the CCBE1 protein and extracellular matrix remodeling and migration. Our results indicate that seven nsSNPs, rs115982879, rs149792489, rs374941368, rs121908254, rs149531418, rs121908251, and rs372499913, are deleterious in the CCBE1 gene, four (G330E, C102S, C174R, and G107D) of which are the highly deleterious, two of them (G330E and G107D) have never been seen reported in the context of Hennekam syndrome. Twelve missense SNPs, rs199902030, rs267605221, rs37517418, rs80008675, rs116596858, rs116675104, rs121908252, rs147974432, rs147681552, rs192224843, rs139059968, and rs148498685, are found to revert into stop codons. Structural homology-based methods and sequence homology-based tools revealed that 8.8% of the nsSNPs are pathogenic. SIFT, PolyPhen2, M-CAP, CADD, FATHMM-MKL, DANN, PANTHER, Mutation Taster, LRT, and SNAP2 had a significant score for identifying deleterious nsSNPs. The importance of rs374941368 and rs200149541 in the prediction of post-translation changes was highlighted because it impacts a possible phosphorylation site. Gene-gene interactions revealed CCBE1's association with other genes, showing its role in a number of pathways and coexpressions. The top 16 deleterious nsSNPs found in this research should be investigated further in the future while researching diseases caused CCBE1 gene specifically HS. The FT web server predicted amino acid residues involved in the ligand-binding site of the CCBE1 protein, and two of the substitutions (R167W and T153N) were found to be involved. These highly deleterious nsSNPs can be used as marker pathogenic variants in the mutational diagnosis of the HS syndrome, and this research also offers potential insights that will aid in the development of precision medicines. CCBE1 proteins from Hennekam syndrome patients should be tested in animal models for this purpose.

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In silico analysis predicting effects of deleterious SNPs of human RASSF5 gene on its structure and functions.

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In silico analysis predicting effects of deleterious SNPs of human RASSF5 gene on its structure and functions.

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