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Functional and Structural Consequences of Damaging Single Nucleotide Polymorphisms in Human Prostate Cancer Predisposition Gene RNASEL.

Datta A, Mazumder MH, Chowdhury AS, Hasan MA - Biomed Res Int (2015)

Bottom Line: By analyzing six tools having different perspectives an aggregate result was produced where nine nsSNPs were found to be most likely to exert deleterious effect. 3D models of mutated proteins were generated to determine the functional and structural effect of the mutations on ribonuclease L.The initial findings were reinforced by the results from I-Mutant and Project HOPE as these tools predicted significant structural and functional instability of the mutated proteins.Considering previous analysis this study revealed a conclusive result deducing the available SNP data on the database by identifying the most damaging three nsSNP rs151296858 (G59S), rs145415894 (A276V), and rs35896902 (R592H).

View Article: PubMed Central - PubMed

Affiliation: Department of Genetic Engineering and Biotechnology, Faculty of Biological Sciences, University of Chittagong, Chittagong 4331, Bangladesh.

ABSTRACT
A commonly diagnosed cancer, prostate cancer (PrCa), is being regulated by the gene RNASEL previously known as PRCA1 codes for ribonuclease L which is an integral part of interferon regulated system that mediates antiviral and antiproliferative role of the interferons. Both somatic and germline mutations have been implicated to cause prostate cancer. With an array of available Single Nucleotide Polymorphism data on dbSNP this study is designed to sort out functional SNPs in RNASEL by implementing different authentic computational tools such as SIFT, PolyPhen, SNPs&GO, Fathmm, ConSurf, UTRScan, PDBsum, Tm-Align, I-Mutant, and Project HOPE for functional and structural assessment, solvent accessibility, molecular dynamics, and energy minimization study. Among 794 RNASEL SNP entries 124 SNPs were found nonsynonymous from which SIFT predicted 13 nsSNPs as nontolerable whereas PolyPhen-2 predicted 28. SNPs found on the 3' and 5' UTR were also assessed. By analyzing six tools having different perspectives an aggregate result was produced where nine nsSNPs were found to be most likely to exert deleterious effect. 3D models of mutated proteins were generated to determine the functional and structural effect of the mutations on ribonuclease L. The initial findings were reinforced by the results from I-Mutant and Project HOPE as these tools predicted significant structural and functional instability of the mutated proteins. Expasy-ProSit tool defined the mutations to be situated in the functional domains of the protein. Considering previous analysis this study revealed a conclusive result deducing the available SNP data on the database by identifying the most damaging three nsSNP rs151296858 (G59S), rs145415894 (A276V), and rs35896902 (R592H). As such studies involving polymorphisms of RNASEL were none to be found, the results of the current study would certainly be helpful in future prospects concerning prostate cancer in males.

No MeSH data available.


Related in: MedlinePlus

Close-up of the mutation A276V. The protein is colored grey; the side chains of both the wild type (Alanine) and the mutant (Valine) residue are shown and colored green and red, respectively.
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fig6: Close-up of the mutation A276V. The protein is colored grey; the side chains of both the wild type (Alanine) and the mutant (Valine) residue are shown and colored green and red, respectively.

Mentions: Similar destabilizing condition is created by the mutation P62S. Replacing a buried Proline with a smaller Serine residue creates a hollow space in the core of the domain that might disturb the function of the domain as shown in Figure 3. In ANK6 repeat region mutation L184S also introduces a smaller residue than the wild type and the result alters the repeat region and hampers the function. The mutations are shown in Figure 4. The next mutation (L224P) disrupts an alpha helix in the protein located in ANK6 repeat. As the mutated residue is located on the surface of a binding domain and is smaller in size than the wild type it is likely to disturb the external interaction of the domain (Figure 5). Mutation A276V replaces Alanine residue on an ankyrin repeat domain (ANK8) to Valine. Valine is larger than Alanine which is buried and the size difference will probably hamper the core structure of the protein (Figure 6).


Functional and Structural Consequences of Damaging Single Nucleotide Polymorphisms in Human Prostate Cancer Predisposition Gene RNASEL.

Datta A, Mazumder MH, Chowdhury AS, Hasan MA - Biomed Res Int (2015)

Close-up of the mutation A276V. The protein is colored grey; the side chains of both the wild type (Alanine) and the mutant (Valine) residue are shown and colored green and red, respectively.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4510121&req=5

fig6: Close-up of the mutation A276V. The protein is colored grey; the side chains of both the wild type (Alanine) and the mutant (Valine) residue are shown and colored green and red, respectively.
Mentions: Similar destabilizing condition is created by the mutation P62S. Replacing a buried Proline with a smaller Serine residue creates a hollow space in the core of the domain that might disturb the function of the domain as shown in Figure 3. In ANK6 repeat region mutation L184S also introduces a smaller residue than the wild type and the result alters the repeat region and hampers the function. The mutations are shown in Figure 4. The next mutation (L224P) disrupts an alpha helix in the protein located in ANK6 repeat. As the mutated residue is located on the surface of a binding domain and is smaller in size than the wild type it is likely to disturb the external interaction of the domain (Figure 5). Mutation A276V replaces Alanine residue on an ankyrin repeat domain (ANK8) to Valine. Valine is larger than Alanine which is buried and the size difference will probably hamper the core structure of the protein (Figure 6).

Bottom Line: By analyzing six tools having different perspectives an aggregate result was produced where nine nsSNPs were found to be most likely to exert deleterious effect. 3D models of mutated proteins were generated to determine the functional and structural effect of the mutations on ribonuclease L.The initial findings were reinforced by the results from I-Mutant and Project HOPE as these tools predicted significant structural and functional instability of the mutated proteins.Considering previous analysis this study revealed a conclusive result deducing the available SNP data on the database by identifying the most damaging three nsSNP rs151296858 (G59S), rs145415894 (A276V), and rs35896902 (R592H).

View Article: PubMed Central - PubMed

Affiliation: Department of Genetic Engineering and Biotechnology, Faculty of Biological Sciences, University of Chittagong, Chittagong 4331, Bangladesh.

ABSTRACT
A commonly diagnosed cancer, prostate cancer (PrCa), is being regulated by the gene RNASEL previously known as PRCA1 codes for ribonuclease L which is an integral part of interferon regulated system that mediates antiviral and antiproliferative role of the interferons. Both somatic and germline mutations have been implicated to cause prostate cancer. With an array of available Single Nucleotide Polymorphism data on dbSNP this study is designed to sort out functional SNPs in RNASEL by implementing different authentic computational tools such as SIFT, PolyPhen, SNPs&GO, Fathmm, ConSurf, UTRScan, PDBsum, Tm-Align, I-Mutant, and Project HOPE for functional and structural assessment, solvent accessibility, molecular dynamics, and energy minimization study. Among 794 RNASEL SNP entries 124 SNPs were found nonsynonymous from which SIFT predicted 13 nsSNPs as nontolerable whereas PolyPhen-2 predicted 28. SNPs found on the 3' and 5' UTR were also assessed. By analyzing six tools having different perspectives an aggregate result was produced where nine nsSNPs were found to be most likely to exert deleterious effect. 3D models of mutated proteins were generated to determine the functional and structural effect of the mutations on ribonuclease L. The initial findings were reinforced by the results from I-Mutant and Project HOPE as these tools predicted significant structural and functional instability of the mutated proteins. Expasy-ProSit tool defined the mutations to be situated in the functional domains of the protein. Considering previous analysis this study revealed a conclusive result deducing the available SNP data on the database by identifying the most damaging three nsSNP rs151296858 (G59S), rs145415894 (A276V), and rs35896902 (R592H). As such studies involving polymorphisms of RNASEL were none to be found, the results of the current study would certainly be helpful in future prospects concerning prostate cancer in males.

No MeSH data available.


Related in: MedlinePlus