In silico evaluation of missense SNPs in cancer-associated Cystatin A protein and their potential to disrupt Cathepsin B interaction
Cystatin A (CSTA) functions as a cysteine protease inhibitor by forming tight complexes with the cathepsins. Pathogenic mutations in the CSTA gene can disrupt this interaction, potentially leading to physiological ailments. In this study, eight bioinformatics tools (SIFT, PolyPhen-2, PROVEAN, P-Mut,...
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Elsevier
2025-02-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844025008588 |
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| author | Shafaat Hossain Omar Hamza Bin Manjur Mst Sharmin Sultana Shimu Tamanna Sultana Mustafizur Rahman Naim Shahariar Siddique Abdullah Al Mamun Md Miftaur Rahman Md Abu Saleh Md Rakibul Hasan Tania Rahman |
| author_facet | Shafaat Hossain Omar Hamza Bin Manjur Mst Sharmin Sultana Shimu Tamanna Sultana Mustafizur Rahman Naim Shahariar Siddique Abdullah Al Mamun Md Miftaur Rahman Md Abu Saleh Md Rakibul Hasan Tania Rahman |
| author_sort | Shafaat Hossain |
| collection | DOAJ |
| description | Cystatin A (CSTA) functions as a cysteine protease inhibitor by forming tight complexes with the cathepsins. Pathogenic mutations in the CSTA gene can disrupt this interaction, potentially leading to physiological ailments. In this study, eight bioinformatics tools (SIFT, PolyPhen-2, PROVEAN, P-Mut, MutPred2, SNAP2, SNPs & GO, and PHD-SNP) were implemented to analyze non-synonymous SNPs from the dbSNP database. Five mutations (Y43C, Y43N, V48F, Y53H, and E94K) located in the conserved region were found to be highly deleterious and less stabilizing. The protein-protein interaction network found that Cathepsin B (CTSB) interacts highly with CSTA. Mutated CSTAs were created by homology modeling, and their altered binding with CTSB was examined through molecular docking and dynamics simulations. Among these, the Y53H (rs1448459675) and E94K (rs200394711) mutants were recognized as weaker inhibitors because they had 2.5 % and an 8 % lower binding affinity, respectively. Moreover, the E94K-CTSB complex, with a root mean square deviation (RMSD) above 5 Å, was found to be highly unstable during molecular dynamics. The root mean square fluctuation (RMSF) of the E94K mutant showed insufficient flexibility, indicating a reduced capacity to suppress CTSB. These findings suggest that the E94K mutation could affect the protein structure and cathepsin B interaction, potentially leading to pathological consequences as evidenced by colorectal adenocarcinoma patients in the COSMIC (Catalogue of Somatic Mutations in Cancer) database. |
| format | Article |
| id | doaj-art-77fd6047a2de4e81a0c1e44bada028ec |
| institution | Kabale University |
| issn | 2405-8440 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Heliyon |
| spelling | doaj-art-77fd6047a2de4e81a0c1e44bada028ec2025-02-09T05:00:42ZengElsevierHeliyon2405-84402025-02-01113e42478In silico evaluation of missense SNPs in cancer-associated Cystatin A protein and their potential to disrupt Cathepsin B interactionShafaat Hossain0Omar Hamza Bin Manjur1Mst Sharmin Sultana Shimu2Tamanna Sultana3Mustafizur Rahman Naim4Shahariar Siddique5Abdullah Al Mamun6Md Miftaur Rahman7Md Abu Saleh8Md Rakibul Hasan9Tania Rahman10Department of Biology & Biochemistry, University of Houston, USADepartment of Biochemistry & Molecular Biology, University of Dhaka, Bangladesh; Bangladesh Reference Institute for Chemical Measurements (BRiCM), BangladeshDepartment of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi, BangladeshDepartment of Biochemistry & Molecular Biology, University of Dhaka, BangladeshBiomedical and Toxicological Research Institute (BTRI), Bangladesh Council of Scientific and Industrial Research (BCSIR), Dhaka, BangladeshInstitute of Food Science and Technology (IFST), Bangladesh Council of Scientific and Industrial Research (BCSIR), Dhaka, BangladeshDepartment of Biochemistry & Biotechnology, University of Science and Technology, Chittagong, Bangladesh; Institute of Technology Transfer and Innovation (ITTI), Bangladesh Council of Scientific and Industrial Research (BCSIR), Dhaka, BangladeshBangladesh Dental College, Dhaka, BangladeshDepartment of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi, BangladeshInstitute of Technology Transfer and Innovation (ITTI), Bangladesh Council of Scientific and Industrial Research (BCSIR), Dhaka, BangladeshDepartment of Biochemistry & Molecular Biology, University of Dhaka, Bangladesh; Corresponding author.Cystatin A (CSTA) functions as a cysteine protease inhibitor by forming tight complexes with the cathepsins. Pathogenic mutations in the CSTA gene can disrupt this interaction, potentially leading to physiological ailments. In this study, eight bioinformatics tools (SIFT, PolyPhen-2, PROVEAN, P-Mut, MutPred2, SNAP2, SNPs & GO, and PHD-SNP) were implemented to analyze non-synonymous SNPs from the dbSNP database. Five mutations (Y43C, Y43N, V48F, Y53H, and E94K) located in the conserved region were found to be highly deleterious and less stabilizing. The protein-protein interaction network found that Cathepsin B (CTSB) interacts highly with CSTA. Mutated CSTAs were created by homology modeling, and their altered binding with CTSB was examined through molecular docking and dynamics simulations. Among these, the Y53H (rs1448459675) and E94K (rs200394711) mutants were recognized as weaker inhibitors because they had 2.5 % and an 8 % lower binding affinity, respectively. Moreover, the E94K-CTSB complex, with a root mean square deviation (RMSD) above 5 Å, was found to be highly unstable during molecular dynamics. The root mean square fluctuation (RMSF) of the E94K mutant showed insufficient flexibility, indicating a reduced capacity to suppress CTSB. These findings suggest that the E94K mutation could affect the protein structure and cathepsin B interaction, potentially leading to pathological consequences as evidenced by colorectal adenocarcinoma patients in the COSMIC (Catalogue of Somatic Mutations in Cancer) database.http://www.sciencedirect.com/science/article/pii/S2405844025008588Stefin ADockingMolecular dynamicsHomology modelingMetastasisCOSMIC |
| spellingShingle | Shafaat Hossain Omar Hamza Bin Manjur Mst Sharmin Sultana Shimu Tamanna Sultana Mustafizur Rahman Naim Shahariar Siddique Abdullah Al Mamun Md Miftaur Rahman Md Abu Saleh Md Rakibul Hasan Tania Rahman In silico evaluation of missense SNPs in cancer-associated Cystatin A protein and their potential to disrupt Cathepsin B interaction Heliyon Stefin A Docking Molecular dynamics Homology modeling Metastasis COSMIC |
| title | In silico evaluation of missense SNPs in cancer-associated Cystatin A protein and their potential to disrupt Cathepsin B interaction |
| title_full | In silico evaluation of missense SNPs in cancer-associated Cystatin A protein and their potential to disrupt Cathepsin B interaction |
| title_fullStr | In silico evaluation of missense SNPs in cancer-associated Cystatin A protein and their potential to disrupt Cathepsin B interaction |
| title_full_unstemmed | In silico evaluation of missense SNPs in cancer-associated Cystatin A protein and their potential to disrupt Cathepsin B interaction |
| title_short | In silico evaluation of missense SNPs in cancer-associated Cystatin A protein and their potential to disrupt Cathepsin B interaction |
| title_sort | in silico evaluation of missense snps in cancer associated cystatin a protein and their potential to disrupt cathepsin b interaction |
| topic | Stefin A Docking Molecular dynamics Homology modeling Metastasis COSMIC |
| url | http://www.sciencedirect.com/science/article/pii/S2405844025008588 |
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