Structural, functional and molecular dynamics analysis of cathepsin B gene SNPs associated with tropical calcific pancreatitis, a rare disease of tropics
Tropical Calcific Pancreatitis (TCP) is a neglected juvenile form of chronic non-alcoholic pancreatitis. Cathepsin B (CTSB), a lysosomal protease involved in the cellular degradation process, has recently been studied as a potential candidate gene in the pathogenesis of TCP. According to the Catheps...
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PeerJ Inc.
2019-10-01
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| author | Garima Singh Sri Krishna jayadev Magani Rinku Sharma Basharat Bhat Ashish Shrivastava Madhusudhan Chinthakindi Ashutosh Singh |
| author_facet | Garima Singh Sri Krishna jayadev Magani Rinku Sharma Basharat Bhat Ashish Shrivastava Madhusudhan Chinthakindi Ashutosh Singh |
| author_sort | Garima Singh |
| collection | DOAJ |
| description | Tropical Calcific Pancreatitis (TCP) is a neglected juvenile form of chronic non-alcoholic pancreatitis. Cathepsin B (CTSB), a lysosomal protease involved in the cellular degradation process, has recently been studied as a potential candidate gene in the pathogenesis of TCP. According to the Cathepsin B hypothesis, mutated CTSB can lead to premature intracellular activation of trypsinogen, a key regulatory mechanism in pancreatitis. So far, CTSB mutations have been studied in pancreatitis and neurodegenerative disorders, but little is known about the structural and functional effect of variants in CTSB. In this study, we investigated the effect of single nucleotide variants (SNVs) specifically associated with TCP, using molecular dynamics and simulation algorithms. There were two non-synonymous variants (L26V and S53G) of CTSB, located in the propeptide region. We tried to predict the effect of these variants on structure and function using multiple algorithms: SIFT, Polyphen2, PANTHER, SDM sever, i-Mutant2.0 suite, mCSM algorithm, and Vadar. Further, using databases like miRdbSNP, PolymiRTS, and miRNASNP, two SNPs in the 3′UTR region were predicted to affect the miRNA binding sites. Structural mutated models of nsSNP mutants (L26V and S53G) were prepared by MODELLER v9.15 and evaluated using TM-Align, Verify 3D, ProSA and Ramachandran plot. The 3D mutated structures were simulated using GROMACS 5.0 to predict the impact of these SNPs on protein stability. The results from in silico analysis and molecular dynamics simulations suggested that these variants in the propeptide region of Cathepsin B could lead to structural and functional changes in the protein and thus could be pathogenic. Hence, the structural and functional analysis results have given interim conclusions that these variants can have a deleterious effect in TCP pathogenesis, either uniquely or in combination with other mutations. Thus, it could be extrapolated that Cathepsin B gene can be screened in samples from all TCP patients in future, to decipher the distribution of variants in patients. |
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| institution | Directory Open Access Journal |
| issn | 2167-8359 |
| language | English |
| last_indexed | 2024-03-09T06:45:49Z |
| publishDate | 2019-10-01 |
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| spelling | doaj.art-eb143d08a60042129365d912a023425f2023-12-03T10:37:07ZengPeerJ Inc.PeerJ2167-83592019-10-017e742510.7717/peerj.7425Structural, functional and molecular dynamics analysis of cathepsin B gene SNPs associated with tropical calcific pancreatitis, a rare disease of tropicsGarima Singh0Sri Krishna jayadev Magani1Rinku Sharma2Basharat Bhat3Ashish Shrivastava4Madhusudhan Chinthakindi5Ashutosh Singh6Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, Greater Noida, Uttar Pradesh, IndiaDepartment of Life Sciences, School of Natural Sciences, Shiv Nadar University, Greater Noida, Uttar Pradesh, IndiaDepartment of Life Sciences, School of Natural Sciences, Shiv Nadar University, Greater Noida, Uttar Pradesh, IndiaDepartment of Life Sciences, School of Natural Sciences, Shiv Nadar University, Greater Noida, Uttar Pradesh, IndiaDepartment of Life Sciences, School of Natural Sciences, Shiv Nadar University, Greater Noida, Uttar Pradesh, IndiaDepartment of Surgical Gastroenterology, Osmania General Hospital, Hyderabad, IndiaDepartment of Life Sciences, School of Natural Sciences, Shiv Nadar University, Greater Noida, Uttar Pradesh, IndiaTropical Calcific Pancreatitis (TCP) is a neglected juvenile form of chronic non-alcoholic pancreatitis. Cathepsin B (CTSB), a lysosomal protease involved in the cellular degradation process, has recently been studied as a potential candidate gene in the pathogenesis of TCP. According to the Cathepsin B hypothesis, mutated CTSB can lead to premature intracellular activation of trypsinogen, a key regulatory mechanism in pancreatitis. So far, CTSB mutations have been studied in pancreatitis and neurodegenerative disorders, but little is known about the structural and functional effect of variants in CTSB. In this study, we investigated the effect of single nucleotide variants (SNVs) specifically associated with TCP, using molecular dynamics and simulation algorithms. There were two non-synonymous variants (L26V and S53G) of CTSB, located in the propeptide region. We tried to predict the effect of these variants on structure and function using multiple algorithms: SIFT, Polyphen2, PANTHER, SDM sever, i-Mutant2.0 suite, mCSM algorithm, and Vadar. Further, using databases like miRdbSNP, PolymiRTS, and miRNASNP, two SNPs in the 3′UTR region were predicted to affect the miRNA binding sites. Structural mutated models of nsSNP mutants (L26V and S53G) were prepared by MODELLER v9.15 and evaluated using TM-Align, Verify 3D, ProSA and Ramachandran plot. The 3D mutated structures were simulated using GROMACS 5.0 to predict the impact of these SNPs on protein stability. The results from in silico analysis and molecular dynamics simulations suggested that these variants in the propeptide region of Cathepsin B could lead to structural and functional changes in the protein and thus could be pathogenic. Hence, the structural and functional analysis results have given interim conclusions that these variants can have a deleterious effect in TCP pathogenesis, either uniquely or in combination with other mutations. Thus, it could be extrapolated that Cathepsin B gene can be screened in samples from all TCP patients in future, to decipher the distribution of variants in patients.https://peerj.com/articles/7425.pdfTropical Calcific PancreatitisPancreatitisCathepsin BMolecular dynamic simulationSingle nucleotide variants |
| spellingShingle | Garima Singh Sri Krishna jayadev Magani Rinku Sharma Basharat Bhat Ashish Shrivastava Madhusudhan Chinthakindi Ashutosh Singh Structural, functional and molecular dynamics analysis of cathepsin B gene SNPs associated with tropical calcific pancreatitis, a rare disease of tropics PeerJ Tropical Calcific Pancreatitis Pancreatitis Cathepsin B Molecular dynamic simulation Single nucleotide variants |
| title | Structural, functional and molecular dynamics analysis of cathepsin B gene SNPs associated with tropical calcific pancreatitis, a rare disease of tropics |
| title_full | Structural, functional and molecular dynamics analysis of cathepsin B gene SNPs associated with tropical calcific pancreatitis, a rare disease of tropics |
| title_fullStr | Structural, functional and molecular dynamics analysis of cathepsin B gene SNPs associated with tropical calcific pancreatitis, a rare disease of tropics |
| title_full_unstemmed | Structural, functional and molecular dynamics analysis of cathepsin B gene SNPs associated with tropical calcific pancreatitis, a rare disease of tropics |
| title_short | Structural, functional and molecular dynamics analysis of cathepsin B gene SNPs associated with tropical calcific pancreatitis, a rare disease of tropics |
| title_sort | structural functional and molecular dynamics analysis of cathepsin b gene snps associated with tropical calcific pancreatitis a rare disease of tropics |
| topic | Tropical Calcific Pancreatitis Pancreatitis Cathepsin B Molecular dynamic simulation Single nucleotide variants |
| url | https://peerj.com/articles/7425.pdf |
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