Identification of functional SNPs in human LGALS3 gene by in silico analyses

Kaur, Tarnjeet; Thakur, Kshema; Singh, Jatinder; Kamboj, Sukhdev Singh; Kaur, Manpreet

doi:10.1016/j.ejmhg.2017.02.001

Cited by 15 publications

(5 citation statements)

References 42 publications

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“…Loss of H-bond in mutant complex signified its weak binding interaction with ubiquitin as well as its structural deformation. We found several studies (70, 77–79) where they did not performed molecular docking and MD simulations for observing changes in interaction pattern as well as stability of a protein after point mutation. Principal component analysis obtained from MD simulation hints at the aberrant structural and functional activity of CYLD due to the point mutation at 827 and 830 position.…”

Section: Discussionmentioning

confidence: 99%

A Computational Approach for Structural and Functional Analyses of Disease-associated Mutations in the HumanCYLDGene

Roy,

Feroz,

Islam

et al. 2023

Preprint

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Tumor suppressor Cylindromatosis protein (CYLD) regulates NF- κB and JNK signaling pathway by cleaving K63 linked poly-ubiquitin chain from its substrate molecules and thus preventing the progression of tumorigenesis and metastasis of the cancer cells. Mutations in CYLD can cause aberrant structure and abnormal functionality leading to tumor formation. In this study, we utilized several computational tools such as PANTHER, PROVEAN, PREDICT- SNP, POLYPHEN 2, PHD SNP, PON P2, and SIFT to find out deleterious nsSNPs. We also highlighted the damaging impact of those deleterious nsSNPs on the structure and function of the CYLD utilizing Consurf, I-Mutant, SDM, Phyre2, HOPE, Swiss PDB Viewer, and Mutation 3D. We shortlisted 18 high-risk nsSNPs from a total of 446 nsSNPs recorded in the NCBI database. Based on the conservation profile, stability status, and structural impact analysis we finalized 13nsSNPs. Molecular docking analysis and molecular dynamic simulation concluded the study with the findings of two significant nsSNPs (R830K, H827R) which have a remarkable impact on binding affinity, RMSD, RMSF, Radius of gyration, and hydrogen bond formation during CYLD-ubiquitin interaction. The principal component analysis compared native and two mutants R830K, H827R of CYLD that signifies structural and energy profile fluctuations during molecular dynamic (MD) simulation. Finally, the Protein-protein interaction network showed CYLD interacts with 20 proteins involved in several biological pathways that mutations can impair. Considering all these in silico analyses, our study recommended conducting large-scale association studies of nsSNPs of CYLD with cancer as well as designing precise medications against diseases associated with these polymorphisms.

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Section: Discussionmentioning

confidence: 99%

A Computational Approach for Structural and Functional Analyses of Disease-associated Mutations in the HumanCYLDGene

Roy,

Feroz,

Islam

et al. 2023

Preprint

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“…Increasing evidence has suggested that SNPs are important and valuable in the search for the etiologies of human diseases/traits, the drug design, and human drug response [ 29 , 30 ]. But the large number of SNPs causes a challenge for scientists because studying all SNPs with molecular approaches to choose target SNPs is an expensive, time-consuming and laborious task [ 29 , 31 , 32 ]. A better sense of genetic variations in susceptibility to disease and their phenotypic effects and reducing the number of them that should be screened in molecular studies may be provided by applying in silico methods [ 26 , 33 ].…”

Section: Discussionmentioning

confidence: 99%

“…For the rational prioritization of the selected most deleterious SNPs for further studies, an analysis of the evolutionary conservation of selected missense mutations was performed by ConSurf. The amino acids at the conserved regions of protein across species are biologically and functionally very important and SNPs that alter these amino acids may lead to structural and functional changes in the protein [ 29 , 31 ]. We have shown that the selected deleterious SNPs in HLA-G1, HLA-G5, the membrane isoforms and the soluble isoforms were mostly in conserved positions and were functional and structural residues, which indicate these SNPs can be deleterious.…”

Section: Discussionmentioning

confidence: 99%

Predicting the most deleterious missense nsSNPs of the protein isoforms of the human HLA-G gene and in silico evaluation of their structural and functional consequences

et al. 2020

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Background: The Human Leukocyte Antigen G (HLA-G) protein is an immune tolerogenic molecule with 7 isoforms. The change of expression level and some polymorphisms of the HLA-G gene are involved in various pathologies. Therefore, this study aimed to predict the most deleterious missense non-synonymous single nucleotide polymorphisms (nsSNPs) in HLA-G isoforms via in silico analyses and to examine structural and functional effects of the predicted nsSNPs on HLA-G isoforms. Results: Out of 301 reported SNPs in dbSNP, 35 missense SNPs in isoform 1, 35 missense SNPs in isoform 5, 8 missense SNPs in all membrane-bound HLA-G isoforms and 8 missense SNPs in all soluble HLA-G isoforms were predicted as deleterious by all eight servers (SIFT, PROVEAN, PolyPhen-2, I-Mutant 3.0, SNPs&GO, PhD-SNP, SNAP2, and MUpro). The Structural and functional effects of the predicted nsSNPs on HLA-G isoforms were determined by MutPred2 and HOPE servers, respectively. Consurf analyses showed that the majority of the predicted nsSNPs occur in conserved sites. I-TASSER and Chimera were used for modeling of the predicted nsSNPs. rs182801644 and rs771111444 were related to creating functional patterns in 5′UTR. 5 SNPs in 3′UTR of the HLA-G gene were predicted to affect the miRNA target sites. Kaplan-Meier analysis showed the HLA-G deregulation can serve as a prognostic marker for some cancers. Conclusions: The implementation of in silico SNP prioritization methods provides a great framework for the recognition of functional SNPs. The results obtained from the current study would be called laboratory investigations.

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“…PATHER-position-specific evolutionary preservation, version 17.0 (PANTHER-PSEP) is a web-based tool ( http://www.pantherdb.org/tools/csnpScoreForm.jsp ) [ 27 ], which is used for the prediction of damaging missense or non-synonymous mutations [ 27 ]. The prediction of this server is based on the position of amino acid variations with a particular value of evolutionary conservation, which is estimated from the sequence alignment of various evolutionary-linked proteins [ 28 ]. FASTA sequence of protein and amino acid substitutions was submitted in the PANTHER-PSEP server for the prediction of the damaging effect of substitutions.…”

Section: Methodsmentioning

confidence: 99%

An In silico Approach towards Finding the Cancer-Causing Mutations in Human MET Gene

Laskar,

Bappy,

Hossain

et al. 2023

International Journal of Genomics

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Mesenchymal–epithelial transition (MET) factor is a proto-oncogene encoding tyrosine kinase receptor with hepatocyte growth factor (HGF) or scatter factor (SF). It is found on the human chromosome number 7 and regulates the diverse cellular mechanisms of the human body. The impact of mutations occurring in the MET gene is demonstrated by their detrimental effects on normal cellular functions. These mutations can change the structure and function of MET leading to different diseases such as lung cancer, neck cancer, colorectal cancer, and many other complex syndromes. Hence, the current study focused on finding deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) and their subsequent impact on the protein’s structure and functions, which may contribute to the emergence of cancers. These nsSNPs were first identified utilizing computational tools like SIFT, PROVEAN, PANTHER-PSEP, PolyPhen-2, I-Mutant 2.0, and MUpro. A total of 45359 SNPs of MET gene were accumulated from the database of dbSNP, and among them, 1306 SNPs were identified as non-synonymous or missense variants. Out of all 1306 nsSNPs, 18 were found to be the most deleterious. Moreover, these nsSNPs exhibited substantial effects on structure, binding affinity with ligand, phylogenetic conservation, secondary structure, and post-translational modification sites of MET, which were evaluated using MutPred2, RaptorX, ConSurf, PSIPRED, and MusiteDeep, respectively. Also, these deleterious nsSNPs were accompanied by changes in properties of MET like residue charge, size, and hydrophobicity. These findings along with the docking results are indicating the potency of the identified SNPs to alter the structure and function of the protein, which may lead to the development of cancers. Nonetheless, Genome-wide association study (GWAS) studies and experimental research are required to confirm the analysis of these nsSNPs.

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Identification of functional SNPs in human LGALS3 gene by in silico analyses

Cited by 15 publications

References 42 publications

A Computational Approach for Structural and Functional Analyses of Disease-associated Mutations in the HumanCYLDGene

A Computational Approach for Structural and Functional Analyses of Disease-associated Mutations in the HumanCYLDGene

Predicting the most deleterious missense nsSNPs of the protein isoforms of the human HLA-G gene and in silico evaluation of their structural and functional consequences

An In silico Approach towards Finding the Cancer-Causing Mutations in Human MET Gene

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