Difference between revisions of "Predicting the Effect of SNPs (PKU)"
(→Investigated SNPS) |
(→Investigated SNPS) |
||
Line 22: | Line 22: | ||
== Investigated SNPS == |
== Investigated SNPS == |
||
In the following section, we present the information we gathered for each SNP individually. Summary comments on the methods we used, we placed at subsites. These include the |
In the following section, we present the information we gathered for each SNP individually. Summary comments on the methods we used, we placed at subsites. These include the |
||
− | [[PsiBlast in Big80 (PKU)|PsiBlast Profile]] of our protein, [[PsiPred of Mutated PAH|PsiPred Predictions]] of the mutated sequences, the complete [[Multiple Alignment Mammalian PheOH|Alignment of 22 mammalian homologs to PAH]] and the [[SNP effect predictions (PKU)|SIFT, PolyPhen and SNAP predictions]], but the |
+ | [[PsiBlast in Big80 (PKU)|PsiBlast Profile]] of our protein, [[PsiPred of Mutated PAH|PsiPred Predictions]] of the mutated sequences, the complete [[Multiple Alignment Mammalian PheOH|Alignment of 22 mammalian homologs to PAH]] and the [[SNP effect predictions (PKU)|SIFT, PolyPhen and SNAP predictions]], but the conclusions are repeated below. |
===GLU76GLY=== |
===GLU76GLY=== |
||
As this mutation results in a change from [http://www.biology.arizona.edu/biochemistry/problem_sets/aa/glutamate.html glutamic acid] to [http://www.biology.arizona.edu/biochemistry/problem_sets/aa/Glycine.html glycine] which have some differences in structure as can bee seen in <xr id="fig:mutationGLUGLY"/> we expect this change to be of rather minor effect. Of course glutamic acid is charged under biological conditions and glycine is not, but glycine could be a universal substitution, because it is neither hydrophobic nor hydrophilic. Additionally, as it is the smallest amino acid, it can not produce any sterical problems. Of course it might be that the glycine can not stabilize any structure, which should be present at this residue.We do not have any structural data for this point, but [[Sequence-based_predictions_(PKU)#Results|predictions]] suggest a position either in a helix or at the edge of a sheet structure. We only can rely on the physiochemical properties, for which we would say, that these changes are not drastic enough to cause the disease. If the mutation would have occurred rather near the catalytic site, our judgment would have been different with respect to the strong affinity of glutamic acid to ions, which plays a major role in PheOH-activity. |
As this mutation results in a change from [http://www.biology.arizona.edu/biochemistry/problem_sets/aa/glutamate.html glutamic acid] to [http://www.biology.arizona.edu/biochemistry/problem_sets/aa/Glycine.html glycine] which have some differences in structure as can bee seen in <xr id="fig:mutationGLUGLY"/> we expect this change to be of rather minor effect. Of course glutamic acid is charged under biological conditions and glycine is not, but glycine could be a universal substitution, because it is neither hydrophobic nor hydrophilic. Additionally, as it is the smallest amino acid, it can not produce any sterical problems. Of course it might be that the glycine can not stabilize any structure, which should be present at this residue.We do not have any structural data for this point, but [[Sequence-based_predictions_(PKU)#Results|predictions]] suggest a position either in a helix or at the edge of a sheet structure. We only can rely on the physiochemical properties, for which we would say, that these changes are not drastic enough to cause the disease. If the mutation would have occurred rather near the catalytic site, our judgment would have been different with respect to the strong affinity of glutamic acid to ions, which plays a major role in PheOH-activity. |
||
− | * |
+ | * amino acid changes: [From ''negativly charged, polar, strongly hydrophilic, medium sized'' '''to''' ''neutral, non-polar, non-hydrophilic, small''] |
* BLOSUM62/PAM250/PAM1: -2(-4,+6)/9 (0,12)/4 (0,9865) |
* BLOSUM62/PAM250/PAM1: -2(-4,+6)/9 (0,12)/4 (0,9865) |
||
* PSSM: conserved |
* PSSM: conserved |
||
Line 32: | Line 32: | ||
*SIFT: TOLERATED with a score of 0.18. |
*SIFT: TOLERATED with a score of 0.18. |
||
+ | *PolyPhen: Benign |
||
− | *PolyPhen (HumVar): BENIGN 0.007 (sensitivity: 0.97; specificity: 0.46) |
||
*SNAP: Non-neutral (low reliability) |
*SNAP: Non-neutral (low reliability) |
||
Prediction:[[File:approved.jpg|100px|]] |
Prediction:[[File:approved.jpg|100px|]] |
||
+ | |||
<figure id="fig:mutationGLUGLY"> |
<figure id="fig:mutationGLUGLY"> |
||
<center><small><caption>Aminoacids in the first mutation</caption></small></center> |
<center><small><caption>Aminoacids in the first mutation</caption></small></center> |
||
Line 49: | Line 50: | ||
===SER87ARG=== |
===SER87ARG=== |
||
we expect that this mutation, which causes a change from [http://www.biology.arizona.edu/biochemistry/problem_sets/aa/Serine.html serine] to [http://www.biology.arizona.edu/biochemistry/problem_sets/aa/Arginine.html arginine], has a bigger effect on the protein, than [[#GLU76GLY|the one above]]. With this mutation the strength of the effect depends completely on the location of the amino acid. Both of the amino acids are hydrophilic, but as arginine is one of the ''snorkeling'', because of its rather hydrophobic stem, the changes can be rather serious(<xr id="fig:mutationSERARG"/>). It is predicted to be two positions N-terminal of a helix structure. As the overall change of size and the change in polarity from rather negative to positive and regarding the fact, that arginine is a rather seldom used amino acid (mostly appearing in the catalytic domain for phosphorylated substrates), we would say, that this is rather a disease causing mutation. |
we expect that this mutation, which causes a change from [http://www.biology.arizona.edu/biochemistry/problem_sets/aa/Serine.html serine] to [http://www.biology.arizona.edu/biochemistry/problem_sets/aa/Arginine.html arginine], has a bigger effect on the protein, than [[#GLU76GLY|the one above]]. With this mutation the strength of the effect depends completely on the location of the amino acid. Both of the amino acids are hydrophilic, but as arginine is one of the ''snorkeling'', because of its rather hydrophobic stem, the changes can be rather serious(<xr id="fig:mutationSERARG"/>). It is predicted to be two positions N-terminal of a helix structure. As the overall change of size and the change in polarity from rather negative to positive and regarding the fact, that arginine is a rather seldom used amino acid (mostly appearing in the catalytic domain for phosphorylated substrates), we would say, that this is rather a disease causing mutation. |
||
− | * |
+ | * amino acid changes: [From ''neutral, polar, slightly hydrophilic'' '''to''' ''pos. charged, polar, strongly hydrophilic''] |
* BLOSUM62/PAM250/PAM1: 1(-3,+4)/11 (1,10(sic!))/6 (1,9840) |
* BLOSUM62/PAM250/PAM1: 1(-3,+4)/11 (1,10(sic!))/6 (1,9840) |
||
* PSSM: residue change appears often |
* PSSM: residue change appears often |
||
Line 55: | Line 56: | ||
*SIFT: TOLERATED with a score of 0.54. |
*SIFT: TOLERATED with a score of 0.54. |
||
+ | *PolyPhen: Benign |
||
− | *PolyPhen (HumVar): BENIGN 0.094 (sensitivity: 0.91; specificity: 0.68) |
||
*SNAP: Non-neutral (low reliability) |
*SNAP: Non-neutral (low reliability) |
||
Line 73: | Line 74: | ||
===ARG158GLN=== |
===ARG158GLN=== |
||
From the secondary structure of both amino acids (<xr id="fig:mutationSERARG"/> left side), one would guess, that if an [http://www.biology.arizona.edu/biochemistry/problem_sets/aa/Arginine.html Arginine] fits in this region, a Glutamine will fit there as well. But if one looks at the right side of this figure, in the close-up there are some small red discs, which indicate sterical collisions. These are due to the additional hydroxl-group, where the original amino acid only had hydrogen-atoms. Depending on the importance of this site and the collision's this mutation can have almost no or a very big effect. But since the sidechain collides in the inside of the protein, we would predict a rather serious effect. |
From the secondary structure of both amino acids (<xr id="fig:mutationSERARG"/> left side), one would guess, that if an [http://www.biology.arizona.edu/biochemistry/problem_sets/aa/Arginine.html Arginine] fits in this region, a Glutamine will fit there as well. But if one looks at the right side of this figure, in the close-up there are some small red discs, which indicate sterical collisions. These are due to the additional hydroxl-group, where the original amino acid only had hydrogen-atoms. Depending on the importance of this site and the collision's this mutation can have almost no or a very big effect. But since the sidechain collides in the inside of the protein, we would predict a rather serious effect. |
||
− | * |
+ | * amino acid changes: [From ''pos. charged, polar, strongly hydrophilic'' '''to''' ''neutral, polar, strongly hydrophilic''] |
* BLOSUM62/PAM250/PAM1: 1(-3,+5)/5 (1,17)/9 (0,9913) |
* BLOSUM62/PAM250/PAM1: 1(-3,+5)/5 (1,17)/9 (0,9913) |
||
* PSSM: residue change appears often |
* PSSM: residue change appears often |
||
Line 79: | Line 80: | ||
*SIFT: AFFECT PROTEIN FUNCTION with a score of 0.00. |
*SIFT: AFFECT PROTEIN FUNCTION with a score of 0.00. |
||
+ | *PolyPhen: Probably Damaging |
||
− | *PolyPhen (HumVar): PROBABLY DAMAGING 1.000 (sensitivity: 0.00; specificity: 1.00) |
||
*SNAP: Non-neutral (high reliability) |
*SNAP: Non-neutral (high reliability) |
||
Line 107: | Line 108: | ||
===GLN172HIS=== |
===GLN172HIS=== |
||
This mutation is rather easy on the first sight. The general chemical properties are the same. The aminoacids only differ in size and structure. As one can see in <xr id="mutationGLNHIS"/> on the right, there are some collisions with the structure. But due to the fact, that this amino acid is located on the outside of the protein and also located in a coiled region which only interferes with another coiled region, we are quite sure, that this mutation is not disease causing. |
This mutation is rather easy on the first sight. The general chemical properties are the same. The aminoacids only differ in size and structure. As one can see in <xr id="mutationGLNHIS"/> on the right, there are some collisions with the structure. But due to the fact, that this amino acid is located on the outside of the protein and also located in a coiled region which only interferes with another coiled region, we are quite sure, that this mutation is not disease causing. |
||
− | * |
+ | * amino acid changes: [From ''neutral, polar, strongly hydrophilic'' '''to''' ''neutral, polar, strongly hydrophilic, ring-structure''] |
* BLOSUM62/PAM250/PAM1: 0(-3,+5)/7 (0,10)/23 (0,9876) |
* BLOSUM62/PAM250/PAM1: 0(-3,+5)/7 (0,10)/23 (0,9876) |
||
* PSSM: residue change appears often |
* PSSM: residue change appears often |
||
Line 113: | Line 114: | ||
*SIFT: AFFECT PROTEIN FUNCTION with a score of 0.03. |
*SIFT: AFFECT PROTEIN FUNCTION with a score of 0.03. |
||
+ | *PolyPhen: Benign |
||
− | *PolyPhen (HumVar): BENIGN 0.170 (sensitivity: 0.89; specificity: 0.72) |
||
*SNAP: Neutral (high reliability) |
*SNAP: Neutral (high reliability) |
||
Line 144: | Line 145: | ||
===ARG243GLN=== |
===ARG243GLN=== |
||
− | From pos. charged, polar, strongly hydrophilic to neutral, polar, strongly hydrophilic. |
+ | * amino acid changes: From pos. charged, polar, strongly hydrophilic to neutral, polar, strongly hydrophilic. |
* BLOSUM62/PAM250/PAM1: 1(-3,+5)/5 (1,17)/9 (0,9913) |
* BLOSUM62/PAM250/PAM1: 1(-3,+5)/5 (1,17)/9 (0,9913) |
||
* PSSM: conserved |
* PSSM: conserved |
||
Line 150: | Line 151: | ||
*SIFT: AFFECT PROTEIN FUNCTION with a score of 0.00. |
*SIFT: AFFECT PROTEIN FUNCTION with a score of 0.00. |
||
+ | *PolyPhen: Probably damaging |
||
− | *PolyPhen (HumVar): PROBABLY DAMAGING 1.000 (sensitivity: 0.00; specificity: 1.00) |
||
*SNAP: Non-neutral (medium reliability) |
*SNAP: Non-neutral (medium reliability) |
||
+ | Prediction:[[File:rejected.jpg|100px|]] |
||
− | |||
+ | <div style="float: left; width: 25%"> |
||
[[File:Pymol_243_close.png|200px|thumb|right|Close-up of the mutated histidine at residue 243 in PheOH. The best fitting rotamer was chosen to minimize severe or smaller collisions (red to green discs) with neighbouring residues. This rotamer appears in 17.3% of mutations according to the PyMol rotamer database.]] |
[[File:Pymol_243_close.png|200px|thumb|right|Close-up of the mutated histidine at residue 243 in PheOH. The best fitting rotamer was chosen to minimize severe or smaller collisions (red to green discs) with neighbouring residues. This rotamer appears in 17.3% of mutations according to the PyMol rotamer database.]] |
||
+ | </div> |
||
+ | <div style="float: left; width: 25%"> |
||
[[File:Pymol_243.png|200px|thumb|right|Mutated glutamine at residue 243 in PheOH. The residue is located in a sheet region.]] |
[[File:Pymol_243.png|200px|thumb|right|Mutated glutamine at residue 243 in PheOH. The residue is located in a sheet region.]] |
||
+ | </div> |
||
+ | <br style="clear:both;"> |
||
===LEU255SER=== |
===LEU255SER=== |
||
− | From neutral, non polar, strongly hydrophobic to neutral, polar, slightly hydrophilic. |
+ | * amino acid changes: From neutral, non polar, strongly hydrophobic to neutral, polar, slightly hydrophilic. |
* BLOSUM62/PAM250/PAM1: -2(-4,+4)/4 (1,34) |
* BLOSUM62/PAM250/PAM1: -2(-4,+4)/4 (1,34) |
||
* PSSM: position variable |
* PSSM: position variable |
||
Line 166: | Line 172: | ||
*SIFT: AFFECT PROTEIN FUNCTION with a score of 0.00. |
*SIFT: AFFECT PROTEIN FUNCTION with a score of 0.00. |
||
+ | *PolyPhen: Probably damaging |
||
− | *PolyPhen (HumVar): PROBABLY DAMAGING 1.000 (sensitivity: 0.00; specificity: 1.00) |
||
*SNAP: Non-neutral (low reliability) |
*SNAP: Non-neutral (low reliability) |
||
+ | Prediction:[[File:rejected.jpg|100px|]] |
||
− | |||
+ | <div style="float: left; width: 25%"> |
||
[[File:Pymol_255_close.png|200px|thumb|right|Close-up of the mutated serine at residue 255 in PheOH. The best fitting rotamer was chosen to minimize severe or smaller collisions (red to green discs) with neighbouring residues. This rotamer appears in 42.9% of mutations according to the PyMol rotamer database.]] |
[[File:Pymol_255_close.png|200px|thumb|right|Close-up of the mutated serine at residue 255 in PheOH. The best fitting rotamer was chosen to minimize severe or smaller collisions (red to green discs) with neighbouring residues. This rotamer appears in 42.9% of mutations according to the PyMol rotamer database.]] |
||
+ | </div> |
||
+ | <div style="float: left; width: 25%"> |
||
[[File:Pymol_255.png|200px|thumb|right|Mutated serine at residue 255 in PheOH. The residue is located in a helix structure.]] |
[[File:Pymol_255.png|200px|thumb|right|Mutated serine at residue 255 in PheOH. The residue is located in a helix structure.]] |
||
+ | </div> |
||
+ | <br style="clear:both;"> |
||
===MET276VAL=== |
===MET276VAL=== |
||
− | From neutral, non-polar, hydrophobic to neutral, non-polar, strongly hydrophobic. |
+ | * amino acid changes: From neutral, non-polar, hydrophobic to neutral, non-polar, strongly hydrophobic. |
* BLOSUM62/PAM250/PAM1: 1(-3,+5)/2 (0,6)/4 (0,9874) |
* BLOSUM62/PAM250/PAM1: 1(-3,+5)/2 (0,6)/4 (0,9874) |
||
* PSSM: residue change appears often |
* PSSM: residue change appears often |
||
Line 182: | Line 193: | ||
*SIFT: TOLERATED with a score of 0.06. |
*SIFT: TOLERATED with a score of 0.06. |
||
+ | *PolyPhen : Benign |
||
− | *PolyPhen (HumVar): BENIGN 0.081 (sensitivity: 0.92; specificity: 0.67) |
||
*SNAP: Neutral (low reliability) |
*SNAP: Neutral (low reliability) |
||
+ | Prediction:[[File:approved.jpg|100px|]] |
||
− | |||
+ | <div style="float: left; width: 25%"> |
||
[[File:Pymol_276_close.png|200px|thumb|right|Close-up of the mutated valine at residue 276 in PheOH. The best fitting rotamer was chosen to minimize severe or smaller collisions (red to green discs) with neighbouring residues. This rotamer appears in 94.5% of mutations according to the PyMol rotamer database.]] |
[[File:Pymol_276_close.png|200px|thumb|right|Close-up of the mutated valine at residue 276 in PheOH. The best fitting rotamer was chosen to minimize severe or smaller collisions (red to green discs) with neighbouring residues. This rotamer appears in 94.5% of mutations according to the PyMol rotamer database.]] |
||
+ | </div> |
||
+ | <div style="float: left; width: 25%"> |
||
[[File:Pymol_276.png|200px|thumb|right|Mutated valine at residue 276 in PheOH. The residue is located in a coil.]] |
[[File:Pymol_276.png|200px|thumb|right|Mutated valine at residue 276 in PheOH. The residue is located in a coil.]] |
||
+ | </div> |
||
− | |||
+ | <br style="clear:both;"> |
||
===ALA322GLY=== |
===ALA322GLY=== |
||
− | From neutral, non-polar, hydrophobic, small to neutral, non-polar, slightly hydrophilic, small. |
+ | * amino acid changes: From neutral, non-polar, hydrophobic, small to neutral, non-polar, slightly hydrophilic, small. |
* BLOSUM62/PAM250/PAM1: 0(-3,+4)/12 (2,13)/21 (0,9876) |
* BLOSUM62/PAM250/PAM1: 0(-3,+4)/12 (2,13)/21 (0,9876) |
||
* PSSM: conserved |
* PSSM: conserved |
||
Line 198: | Line 213: | ||
*SIFT: AFFECT PROTEIN FUNCTION with a score of 0.01. |
*SIFT: AFFECT PROTEIN FUNCTION with a score of 0.01. |
||
+ | *PolyPhen: Possibily damaging |
||
− | *PolyPhen (HumVar): POSSIBLY DAMAGING 0.707 (sensitivity: 0.78; specificity: 0.85) |
||
*SNAP: Neutral (low reliability) |
*SNAP: Neutral (low reliability) |
||
+ | Prediction:[[File:approved.jpg|100px|]] |
||
+ | <div style="float: left; width: 25%"> |
||
[[File:Pymol_322_close.png|200px|thumb|right|Close-up of the mutated glycine at residue 322 in PheOH. There is only one rotamer and there can not be collisions with neighbouring residues as glycine is the smallest amino acid.]] |
[[File:Pymol_322_close.png|200px|thumb|right|Close-up of the mutated glycine at residue 322 in PheOH. There is only one rotamer and there can not be collisions with neighbouring residues as glycine is the smallest amino acid.]] |
||
+ | </div> |
||
+ | <div style="float: left; width: 25%"> |
||
[[File:Pymol_322.png|200px|thumb|right|Mutated glycine at residue 322 in PheOH. The residue is located in a helix region.]] |
[[File:Pymol_322.png|200px|thumb|right|Mutated glycine at residue 322 in PheOH. The residue is located in a helix region.]] |
||
+ | </div> |
||
− | |||
+ | <br style="clear:both;"> |
||
===GLY337VAL=== |
===GLY337VAL=== |
||
− | From neutral, non-polar, slightly hydrophilic, small to neutral, non-polar, strongly hydrophobic, medium sized. |
+ | * amino acid changes: From neutral, non-polar, slightly hydrophilic, small to neutral, non-polar, strongly hydrophobic, medium sized. |
* BLOSUM62/PAM250/PAM1: -3(-4,+6)/4 (0,27)/5 (0,9935) |
* BLOSUM62/PAM250/PAM1: -3(-4,+6)/4 (0,27)/5 (0,9935) |
||
* PSSM: position variable |
* PSSM: position variable |
||
Line 213: | Line 233: | ||
*SIFT: AFFECT PROTEIN FUNCTION with a score of 0.00. |
*SIFT: AFFECT PROTEIN FUNCTION with a score of 0.00. |
||
+ | *PolyPhen: Possibly damaging |
||
− | *PolyPhen (HumVar): POSSIBLY DAMAGING 0.597 (sensitivity: 0.81; specificity: 0.83) |
||
*SNAP: Neutral (low reliability) |
*SNAP: Neutral (low reliability) |
||
+ | Prediction:[[File:rejected.jpg|100px|]] |
||
− | |||
+ | <div style="float: left; width: 25%"> |
||
[[File:Pymol_337_close.png|200px|thumb|right|Close-up of the mutated valine at residue 337 in PheOH. The best fitting rotamer was chosen to minimize severe or smaller collisions (red to green discs) with neighbouring residues. This rotamer appears in 2.9% of mutations according to the PyMol rotamer database.]] |
[[File:Pymol_337_close.png|200px|thumb|right|Close-up of the mutated valine at residue 337 in PheOH. The best fitting rotamer was chosen to minimize severe or smaller collisions (red to green discs) with neighbouring residues. This rotamer appears in 2.9% of mutations according to the PyMol rotamer database.]] |
||
+ | </div> |
||
+ | <div style="float: left; width: 25%"> |
||
[[File:Pymol_337.png|200px|thumb|right|Mutated valine at residue 337 in PheOH. The residue is located in a loop between two sheet elements.]] |
[[File:Pymol_337.png|200px|thumb|right|Mutated valine at residue 337 in PheOH. The residue is located in a loop between two sheet elements.]] |
||
+ | </div> |
||
+ | |||
+ | <br style="clear:both;"> |
||
===ARG408TRP=== |
===ARG408TRP=== |
||
− | From pos. charged, polar, strongly hydrophilic, medium sized to neutral, non-polar, slightly hydrophilic, large. |
+ | * amino acid changes: From pos. charged, polar, strongly hydrophilic, medium sized to neutral, non-polar, slightly hydrophilic, large. |
* BLOSUM62/PAM250/PAM1: -3(-3,+5)/2 (1,17)/ 2 (0, 9913) |
* BLOSUM62/PAM250/PAM1: -3(-3,+5)/2 (1,17)/ 2 (0, 9913) |
||
* PSSM: conserved |
* PSSM: conserved |
||
Line 227: | Line 253: | ||
*SIFT: AFFECT PROTEIN FUNCTION with a score of 0.00. |
*SIFT: AFFECT PROTEIN FUNCTION with a score of 0.00. |
||
+ | *PolyPhen: Probably damaging |
||
− | *PolyPhen (HumVar): PROBABLY DAMAGING 0.999 (sensitivity: 0.09; specificity: 0.99) |
||
*SNAP: Non-neutral (medium reliability) |
*SNAP: Non-neutral (medium reliability) |
||
+ | Prediction:[[File:rejected.jpg|100px|]] |
||
+ | <div style="float: left; width: 25%"> |
||
[[File:Pymol_408_close.png|200px|thumb|right|Close-up of the mutated tryptophan at residue 408 in PheOH. The best fitting rotamer was chosen to minimize severe or smaller collisions (red to green discs) with neighbouring residues. This rotamer appears in 2.3% of mutations according to the PyMol rotamer database.]] |
[[File:Pymol_408_close.png|200px|thumb|right|Close-up of the mutated tryptophan at residue 408 in PheOH. The best fitting rotamer was chosen to minimize severe or smaller collisions (red to green discs) with neighbouring residues. This rotamer appears in 2.3% of mutations according to the PyMol rotamer database.]] |
||
+ | </div> |
||
+ | <div style="float: left; width: 25%"> |
||
[[File:Pymol_408.png|200px|thumb|right|Mutated tryptophan at residue 408 in PheOH. The residue is located in a coil near a helix region.]] |
[[File:Pymol_408.png|200px|thumb|right|Mutated tryptophan at residue 408 in PheOH. The residue is located in a coil near a helix region.]] |
||
+ | </div> |
||
+ | |||
+ | <br style="clear:both;"> |
||
==References== |
==References== |
Revision as of 14:51, 16 June 2012
Contents
Short Introduction
This week's task builds on the data gathered last week. We blindly choose 5 disease causing and 5 harmless SNPs and will try to predict their effect from the sequence change alone. You may find a detailed task description at the usual place and consult our task journal.
Our dataset
we propose the following dataset:
- GLU76GLY
- SER87ARG
- ARG158GLN
- GLN172HIS
- ARG243GLN
- LEU255SER
- MET276VAL
- ALA322GLY
- GLY337VAL
- ARG408TRP
You could check them, if you like.. I put them together 5 minutes ago and already forgot, which are which. ;-)
Investigated SNPS
In the following section, we present the information we gathered for each SNP individually. Summary comments on the methods we used, we placed at subsites. These include the PsiBlast Profile of our protein, PsiPred Predictions of the mutated sequences, the complete Alignment of 22 mammalian homologs to PAH and the SIFT, PolyPhen and SNAP predictions, but the conclusions are repeated below.
GLU76GLY
As this mutation results in a change from glutamic acid to glycine which have some differences in structure as can bee seen in <xr id="fig:mutationGLUGLY"/> we expect this change to be of rather minor effect. Of course glutamic acid is charged under biological conditions and glycine is not, but glycine could be a universal substitution, because it is neither hydrophobic nor hydrophilic. Additionally, as it is the smallest amino acid, it can not produce any sterical problems. Of course it might be that the glycine can not stabilize any structure, which should be present at this residue.We do not have any structural data for this point, but predictions suggest a position either in a helix or at the edge of a sheet structure. We only can rely on the physiochemical properties, for which we would say, that these changes are not drastic enough to cause the disease. If the mutation would have occurred rather near the catalytic site, our judgment would have been different with respect to the strong affinity of glutamic acid to ions, which plays a major role in PheOH-activity.
- amino acid changes: [From negativly charged, polar, strongly hydrophilic, medium sized to neutral, non-polar, non-hydrophilic, small]
- BLOSUM62/PAM250/PAM1: -2(-4,+6)/9 (0,12)/4 (0,9865)
- PSSM: conserved
- Alignment of homologs: some variability
- SIFT: TOLERATED with a score of 0.18.
- PolyPhen: Benign
- SNAP: Non-neutral (low reliability)
<figure id="fig:mutationGLUGLY">
</figure>
SER87ARG
we expect that this mutation, which causes a change from serine to arginine, has a bigger effect on the protein, than the one above. With this mutation the strength of the effect depends completely on the location of the amino acid. Both of the amino acids are hydrophilic, but as arginine is one of the snorkeling, because of its rather hydrophobic stem, the changes can be rather serious(<xr id="fig:mutationSERARG"/>). It is predicted to be two positions N-terminal of a helix structure. As the overall change of size and the change in polarity from rather negative to positive and regarding the fact, that arginine is a rather seldom used amino acid (mostly appearing in the catalytic domain for phosphorylated substrates), we would say, that this is rather a disease causing mutation.
- amino acid changes: [From neutral, polar, slightly hydrophilic to pos. charged, polar, strongly hydrophilic]
- BLOSUM62/PAM250/PAM1: 1(-3,+4)/11 (1,10(sic!))/6 (1,9840)
- PSSM: residue change appears often
- Alignment of homologs: some variability
- SIFT: TOLERATED with a score of 0.54.
- PolyPhen: Benign
- SNAP: Non-neutral (low reliability)
Prediction
<figure id="fig:mutationSERARG">
</figure>
ARG158GLN
From the secondary structure of both amino acids (<xr id="fig:mutationSERARG"/> left side), one would guess, that if an Arginine fits in this region, a Glutamine will fit there as well. But if one looks at the right side of this figure, in the close-up there are some small red discs, which indicate sterical collisions. These are due to the additional hydroxl-group, where the original amino acid only had hydrogen-atoms. Depending on the importance of this site and the collision's this mutation can have almost no or a very big effect. But since the sidechain collides in the inside of the protein, we would predict a rather serious effect.
- amino acid changes: [From pos. charged, polar, strongly hydrophilic to neutral, polar, strongly hydrophilic]
- BLOSUM62/PAM250/PAM1: 1(-3,+5)/5 (1,17)/9 (0,9913)
- PSSM: residue change appears often
- Alignment of homologs: some variability
- SIFT: AFFECT PROTEIN FUNCTION with a score of 0.00.
- PolyPhen: Probably Damaging
- SNAP: Non-neutral (high reliability)
Prediction:
<figure id="fig:mutationSERARG">
</figure>
GLN172HIS
This mutation is rather easy on the first sight. The general chemical properties are the same. The aminoacids only differ in size and structure. As one can see in <xr id="mutationGLNHIS"/> on the right, there are some collisions with the structure. But due to the fact, that this amino acid is located on the outside of the protein and also located in a coiled region which only interferes with another coiled region, we are quite sure, that this mutation is not disease causing.
- amino acid changes: [From neutral, polar, strongly hydrophilic to neutral, polar, strongly hydrophilic, ring-structure]
- BLOSUM62/PAM250/PAM1: 0(-3,+5)/7 (0,10)/23 (0,9876)
- PSSM: residue change appears often
- Alignment of homologs: highly conserved
- SIFT: AFFECT PROTEIN FUNCTION with a score of 0.03.
- PolyPhen: Benign
- SNAP: Neutral (high reliability)
Prediction:
<figure id="mutationGLNHIS">
</figure>
ARG243GLN
- amino acid changes: From pos. charged, polar, strongly hydrophilic to neutral, polar, strongly hydrophilic.
- BLOSUM62/PAM250/PAM1: 1(-3,+5)/5 (1,17)/9 (0,9913)
- PSSM: conserved
- Alignment of homologs: highly conserved
- SIFT: AFFECT PROTEIN FUNCTION with a score of 0.00.
- PolyPhen: Probably damaging
- SNAP: Non-neutral (medium reliability)
LEU255SER
- amino acid changes: From neutral, non polar, strongly hydrophobic to neutral, polar, slightly hydrophilic.
- BLOSUM62/PAM250/PAM1: -2(-4,+4)/4 (1,34)
- PSSM: position variable
- Alignment of homologs: highly conserved
- SIFT: AFFECT PROTEIN FUNCTION with a score of 0.00.
- PolyPhen: Probably damaging
- SNAP: Non-neutral (low reliability)
MET276VAL
- amino acid changes: From neutral, non-polar, hydrophobic to neutral, non-polar, strongly hydrophobic.
- BLOSUM62/PAM250/PAM1: 1(-3,+5)/2 (0,6)/4 (0,9874)
- PSSM: residue change appears often
- Alignment of homologs: highly conserved
- SIFT: TOLERATED with a score of 0.06.
- PolyPhen : Benign
- SNAP: Neutral (low reliability)
ALA322GLY
- amino acid changes: From neutral, non-polar, hydrophobic, small to neutral, non-polar, slightly hydrophilic, small.
- BLOSUM62/PAM250/PAM1: 0(-3,+4)/12 (2,13)/21 (0,9876)
- PSSM: conserved
- Alignment of homologs: highly conserved
- SIFT: AFFECT PROTEIN FUNCTION with a score of 0.01.
- PolyPhen: Possibily damaging
- SNAP: Neutral (low reliability)
GLY337VAL
- amino acid changes: From neutral, non-polar, slightly hydrophilic, small to neutral, non-polar, strongly hydrophobic, medium sized.
- BLOSUM62/PAM250/PAM1: -3(-4,+6)/4 (0,27)/5 (0,9935)
- PSSM: position variable
- Alignment of homologs: some variability
- SIFT: AFFECT PROTEIN FUNCTION with a score of 0.00.
- PolyPhen: Possibly damaging
- SNAP: Neutral (low reliability)
ARG408TRP
- amino acid changes: From pos. charged, polar, strongly hydrophilic, medium sized to neutral, non-polar, slightly hydrophilic, large.
- BLOSUM62/PAM250/PAM1: -3(-3,+5)/2 (1,17)/ 2 (0, 9913)
- PSSM: conserved
- Alignment of homologs: highly conserved
- SIFT: AFFECT PROTEIN FUNCTION with a score of 0.00.
- PolyPhen: Probably damaging
- SNAP: Non-neutral (medium reliability)
References
A helix propensity scale based on experimental studies of peptides and proteins.