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Environment specific substitution tables improve membrane protein alignment.

Hill JR, Kelm S, Shi J, Deane CM - Bioinformatics (2011)

Bottom Line: For example, substitution preferences in lipid tail-contacting parts of membrane proteins are found to be distinct from all environments in soluble proteins, including buried residues.A principal component analysis of the tables identifies the greatest variation in substitution preferences to be due to changes in hydrophobicity; the second largest variation relates to secondary structure.Our alignments also lead to improved structural models.

View Article: PubMed Central - PubMed

Affiliation: Department of Statistics, University of Oxford, 1 South Parks Road, Oxford, OX1 3TG, UK.

ABSTRACT

Motivation: Membrane proteins are both abundant and important in cells, but the small number of solved structures restricts our understanding of them. Here we consider whether membrane proteins undergo different substitutions from their soluble counterparts and whether these can be used to improve membrane protein alignments, and therefore improve prediction of their structure.

Results: We construct substitution tables for different environments within membrane proteins. As data is scarce, we develop a general metric to assess the quality of these asymmetric tables. Membrane proteins show markedly different substitution preferences from soluble proteins. For example, substitution preferences in lipid tail-contacting parts of membrane proteins are found to be distinct from all environments in soluble proteins, including buried residues. A principal component analysis of the tables identifies the greatest variation in substitution preferences to be due to changes in hydrophobicity; the second largest variation relates to secondary structure. We demonstrate the use of our tables in pairwise sequence-to-structure alignments (also known as 'threading') of membrane proteins using the FUGUE alignment program. On average, in the 10-25% sequence identity range, alignments are improved by 28 correctly aligned residues compared with alignments made using FUGUE's default substitution tables. Our alignments also lead to improved structural models.

Availability: Substitution tables are available at: http://www.stats.ox.ac.uk/proteins/resources.

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Related in: MedlinePlus

Principal component analysis of ESSTs. The top row and the bottom row are views of the same data along different principal components. The columns colour-code the data-points by layer type, secondary structure and accessibility, respectively. This allows the three-letter table code of each point to be read off from left to right. The labelled tables are ordered by secondary structure in the second principal component—reading panel (e) from left to right we first encounter TCa, then TEa, then THa. A similar ordering holds for other layer and accessibility types.
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Figure 4: Principal component analysis of ESSTs. The top row and the bottom row are views of the same data along different principal components. The columns colour-code the data-points by layer type, secondary structure and accessibility, respectively. This allows the three-letter table code of each point to be read off from left to right. The labelled tables are ordered by secondary structure in the second principal component—reading panel (e) from left to right we first encounter TCa, then TEa, then THa. A similar ordering holds for other layer and accessibility types.

Mentions: A PCA plot allows patterns in substitutions to be discerned. Figure 4 accounts for 48% of the variation in the data with 3 principal components. Figure 4c shows that the differences between accessible and inaccessible environments cause most of the variation between tables—they are largely separated along the first principal component (the main exceptions being accessible tail-layer tables, T*A). This first component can broadly be identified as a measure of ‘hydrophobicity’. Looking at the labelled points in Figure 4a, as the first principal component increases we move from tail layer to interface layer to head layer accessible environments, corresponding to decreasing hydrophobicity.Fig. 4.


Environment specific substitution tables improve membrane protein alignment.

Hill JR, Kelm S, Shi J, Deane CM - Bioinformatics (2011)

Principal component analysis of ESSTs. The top row and the bottom row are views of the same data along different principal components. The columns colour-code the data-points by layer type, secondary structure and accessibility, respectively. This allows the three-letter table code of each point to be read off from left to right. The labelled tables are ordered by secondary structure in the second principal component—reading panel (e) from left to right we first encounter TCa, then TEa, then THa. A similar ordering holds for other layer and accessibility types.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3117371&req=5

Figure 4: Principal component analysis of ESSTs. The top row and the bottom row are views of the same data along different principal components. The columns colour-code the data-points by layer type, secondary structure and accessibility, respectively. This allows the three-letter table code of each point to be read off from left to right. The labelled tables are ordered by secondary structure in the second principal component—reading panel (e) from left to right we first encounter TCa, then TEa, then THa. A similar ordering holds for other layer and accessibility types.
Mentions: A PCA plot allows patterns in substitutions to be discerned. Figure 4 accounts for 48% of the variation in the data with 3 principal components. Figure 4c shows that the differences between accessible and inaccessible environments cause most of the variation between tables—they are largely separated along the first principal component (the main exceptions being accessible tail-layer tables, T*A). This first component can broadly be identified as a measure of ‘hydrophobicity’. Looking at the labelled points in Figure 4a, as the first principal component increases we move from tail layer to interface layer to head layer accessible environments, corresponding to decreasing hydrophobicity.Fig. 4.

Bottom Line: For example, substitution preferences in lipid tail-contacting parts of membrane proteins are found to be distinct from all environments in soluble proteins, including buried residues.A principal component analysis of the tables identifies the greatest variation in substitution preferences to be due to changes in hydrophobicity; the second largest variation relates to secondary structure.Our alignments also lead to improved structural models.

View Article: PubMed Central - PubMed

Affiliation: Department of Statistics, University of Oxford, 1 South Parks Road, Oxford, OX1 3TG, UK.

ABSTRACT

Motivation: Membrane proteins are both abundant and important in cells, but the small number of solved structures restricts our understanding of them. Here we consider whether membrane proteins undergo different substitutions from their soluble counterparts and whether these can be used to improve membrane protein alignments, and therefore improve prediction of their structure.

Results: We construct substitution tables for different environments within membrane proteins. As data is scarce, we develop a general metric to assess the quality of these asymmetric tables. Membrane proteins show markedly different substitution preferences from soluble proteins. For example, substitution preferences in lipid tail-contacting parts of membrane proteins are found to be distinct from all environments in soluble proteins, including buried residues. A principal component analysis of the tables identifies the greatest variation in substitution preferences to be due to changes in hydrophobicity; the second largest variation relates to secondary structure. We demonstrate the use of our tables in pairwise sequence-to-structure alignments (also known as 'threading') of membrane proteins using the FUGUE alignment program. On average, in the 10-25% sequence identity range, alignments are improved by 28 correctly aligned residues compared with alignments made using FUGUE's default substitution tables. Our alignments also lead to improved structural models.

Availability: Substitution tables are available at: http://www.stats.ox.ac.uk/proteins/resources.

Show MeSH
Related in: MedlinePlus