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coliSNP database server mapping nsSNPs on protein structures.

Kono H, Yuasa T, Nishiue S, Yura K - Nucleic Acids Res. (2007)

Bottom Line: The position of the nsSNP within the amino acid sequence and on the 3D structure of the protein can also be observed.The database provides key information with which to judge whether an observed nsSNP critically affects protein function and/or stability.As far as we know, this is the only web-based nsSNP database that automatically compiles SNP and protein information in a concise manner.

View Article: PubMed Central - PubMed

Affiliation: Computational Biology Group, Quantum Beam Science Directorate, Japan Atomic Energy Agency, 8-1 Umemidai, Kizugawa, Kyoto 619-0215, PRESTO, Japan. kono.hidetoshi@jaea.go.jp

ABSTRACT
We have developed coliSNP, a database server (http://yayoi.kansai.jaea.go.jp/colisnp) that maps non-synonymous single nucleotide polymorphisms (nsSNPs) on the three-dimensional (3D) structure of proteins. Once a week, the SNP data from the dbSNP database and the protein structure data from the Protein Data Bank (PDB) are downloaded, and the correspondence of the two data sets is automatically tabulated in the coliSNP database. Given an amino acid sequence, protein name or PDB ID, the server will immediately provide known nsSNP information, including the amino acid mutation caused by the nsSNP, the solvent accessibility, the secondary structure and the flanking residues of the mutated residue in a single page. The position of the nsSNP within the amino acid sequence and on the 3D structure of the protein can also be observed. The database provides key information with which to judge whether an observed nsSNP critically affects protein function and/or stability. As far as we know, this is the only web-based nsSNP database that automatically compiles SNP and protein information in a concise manner.

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Related in: MedlinePlus

Cumulative plots of tolerant, partially tolerant and intolerant sites in Lac repressor against the solvent accessibility. In the experiment (17), 12 or 13 mutations (depending on the identity of the wild-type residue) were tested at 124 sites. We defined the tolerance at each site as follows: tolerant, <5 of the mutations cause loss of function (45 sites); intolerant, >8 of the mutations cause loss of function (69 sites); and partially tolerant, 5–8 of the mutations cause loss of function (10 sites). The solvent accessibility was calculated using the program ASC (19) with a protein–DNA complex form (PDB:1EFA) or a tetrameric form (PDB:1LBI), depending on the site considered.
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Figure 3: Cumulative plots of tolerant, partially tolerant and intolerant sites in Lac repressor against the solvent accessibility. In the experiment (17), 12 or 13 mutations (depending on the identity of the wild-type residue) were tested at 124 sites. We defined the tolerance at each site as follows: tolerant, <5 of the mutations cause loss of function (45 sites); intolerant, >8 of the mutations cause loss of function (69 sites); and partially tolerant, 5–8 of the mutations cause loss of function (10 sites). The solvent accessibility was calculated using the program ASC (19) with a protein–DNA complex form (PDB:1EFA) or a tetrameric form (PDB:1LBI), depending on the site considered.

Mentions: One of the unique features of the coliSNP database is that it gives the solvent accessibility of a wild-type residue that has been mutated by an nsSNP. We found that the solvent accessibility is the best indicator of the impact of a mutation on protein function. Other properties that we evaluated include the secondary structure where the mutation occurred, changes in hydrogen bonding, and the chemical properties of the affected residue. The correlation between the effect substituting a single residue and its solvent accessibility has long been discussed (14–16). To provide a quantitative limit for the solvent accessibility of residues able to tolerate mutation caused by nsSNPs, we collected experimental data showing the relationship between point mutations and the activities of proteins with known 3D structures. The point mutation studies on Lac repressor (17) and T4 lysozyme (18), in particular, provided us with sufficient data to determine that limit of solvent accessibility. The solvent accessibility was calculated with ASC(19). We then re-examined the relationship between solvent accessibility and viability of the organism for these two proteins. Figure 3 shows the loss of function rate plotted against the solvent accessibility of the wild-type residue. In the case of Lac repressor, about 90% of mutation-tolerant sites (see Figure 3 caption) were located at positions where the solvent accessibility of the wild-type residue was >30%, and about 80% of mutations in intolerant or partially tolerant sites were located at positions where the solvent accessibility was ≤30%. Based on this observation, we decided to provide the solvent accessibility value of the mutated residue together with the 3D structure of the protein in the database, and the residues with solvent accessibility of ≤ 30% were marked in yellow in the 3D structures. We believe that these data enable one to evaluate possible effect of nsSNPs on protein stability and function. For instance, the nsSNP in human SYK kinase shown in Figure 2 results in the substitution of Arg45 with His, and the solvent accessibility is 8%. Because of the degree to which this residue is buried, it is highly likely that the substitution will have a deleterious effect on the protein's function and/or stability, as suggested by Figure 3. In fact, the residue forms one of the loops for domain association and is located relatively close to the phosphorylated Tyr of the target peptide (20). Both of these pieces of information are easily retrieved from coliSNP and may add medically important annotation to the SNP site. It is worth noting that the impact of a mutation should also be evaluated based on sequence conservation. Disease-associated nsSNPs tend to be located at highly conserved sites (21). This information will be incorporated in the coliSNP database in the near future.Figure 3.


coliSNP database server mapping nsSNPs on protein structures.

Kono H, Yuasa T, Nishiue S, Yura K - Nucleic Acids Res. (2007)

Cumulative plots of tolerant, partially tolerant and intolerant sites in Lac repressor against the solvent accessibility. In the experiment (17), 12 or 13 mutations (depending on the identity of the wild-type residue) were tested at 124 sites. We defined the tolerance at each site as follows: tolerant, <5 of the mutations cause loss of function (45 sites); intolerant, >8 of the mutations cause loss of function (69 sites); and partially tolerant, 5–8 of the mutations cause loss of function (10 sites). The solvent accessibility was calculated using the program ASC (19) with a protein–DNA complex form (PDB:1EFA) or a tetrameric form (PDB:1LBI), depending on the site considered.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2238833&req=5

Figure 3: Cumulative plots of tolerant, partially tolerant and intolerant sites in Lac repressor against the solvent accessibility. In the experiment (17), 12 or 13 mutations (depending on the identity of the wild-type residue) were tested at 124 sites. We defined the tolerance at each site as follows: tolerant, <5 of the mutations cause loss of function (45 sites); intolerant, >8 of the mutations cause loss of function (69 sites); and partially tolerant, 5–8 of the mutations cause loss of function (10 sites). The solvent accessibility was calculated using the program ASC (19) with a protein–DNA complex form (PDB:1EFA) or a tetrameric form (PDB:1LBI), depending on the site considered.
Mentions: One of the unique features of the coliSNP database is that it gives the solvent accessibility of a wild-type residue that has been mutated by an nsSNP. We found that the solvent accessibility is the best indicator of the impact of a mutation on protein function. Other properties that we evaluated include the secondary structure where the mutation occurred, changes in hydrogen bonding, and the chemical properties of the affected residue. The correlation between the effect substituting a single residue and its solvent accessibility has long been discussed (14–16). To provide a quantitative limit for the solvent accessibility of residues able to tolerate mutation caused by nsSNPs, we collected experimental data showing the relationship between point mutations and the activities of proteins with known 3D structures. The point mutation studies on Lac repressor (17) and T4 lysozyme (18), in particular, provided us with sufficient data to determine that limit of solvent accessibility. The solvent accessibility was calculated with ASC(19). We then re-examined the relationship between solvent accessibility and viability of the organism for these two proteins. Figure 3 shows the loss of function rate plotted against the solvent accessibility of the wild-type residue. In the case of Lac repressor, about 90% of mutation-tolerant sites (see Figure 3 caption) were located at positions where the solvent accessibility of the wild-type residue was >30%, and about 80% of mutations in intolerant or partially tolerant sites were located at positions where the solvent accessibility was ≤30%. Based on this observation, we decided to provide the solvent accessibility value of the mutated residue together with the 3D structure of the protein in the database, and the residues with solvent accessibility of ≤ 30% were marked in yellow in the 3D structures. We believe that these data enable one to evaluate possible effect of nsSNPs on protein stability and function. For instance, the nsSNP in human SYK kinase shown in Figure 2 results in the substitution of Arg45 with His, and the solvent accessibility is 8%. Because of the degree to which this residue is buried, it is highly likely that the substitution will have a deleterious effect on the protein's function and/or stability, as suggested by Figure 3. In fact, the residue forms one of the loops for domain association and is located relatively close to the phosphorylated Tyr of the target peptide (20). Both of these pieces of information are easily retrieved from coliSNP and may add medically important annotation to the SNP site. It is worth noting that the impact of a mutation should also be evaluated based on sequence conservation. Disease-associated nsSNPs tend to be located at highly conserved sites (21). This information will be incorporated in the coliSNP database in the near future.Figure 3.

Bottom Line: The position of the nsSNP within the amino acid sequence and on the 3D structure of the protein can also be observed.The database provides key information with which to judge whether an observed nsSNP critically affects protein function and/or stability.As far as we know, this is the only web-based nsSNP database that automatically compiles SNP and protein information in a concise manner.

View Article: PubMed Central - PubMed

Affiliation: Computational Biology Group, Quantum Beam Science Directorate, Japan Atomic Energy Agency, 8-1 Umemidai, Kizugawa, Kyoto 619-0215, PRESTO, Japan. kono.hidetoshi@jaea.go.jp

ABSTRACT
We have developed coliSNP, a database server (http://yayoi.kansai.jaea.go.jp/colisnp) that maps non-synonymous single nucleotide polymorphisms (nsSNPs) on the three-dimensional (3D) structure of proteins. Once a week, the SNP data from the dbSNP database and the protein structure data from the Protein Data Bank (PDB) are downloaded, and the correspondence of the two data sets is automatically tabulated in the coliSNP database. Given an amino acid sequence, protein name or PDB ID, the server will immediately provide known nsSNP information, including the amino acid mutation caused by the nsSNP, the solvent accessibility, the secondary structure and the flanking residues of the mutated residue in a single page. The position of the nsSNP within the amino acid sequence and on the 3D structure of the protein can also be observed. The database provides key information with which to judge whether an observed nsSNP critically affects protein function and/or stability. As far as we know, this is the only web-based nsSNP database that automatically compiles SNP and protein information in a concise manner.

Show MeSH
Related in: MedlinePlus