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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

Dendrogram of ESSTs. A split is seen between accessible (red) and inaccessible (blue) environments. Tail-layer environments (T**) appear not to cluster. Note that here, as elsewhere, ‘NPa’ and ‘NPA’ refer to combined +ve ϕ environments that include residues in the transmembrane regions (see Section 3.2).
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Figure 3: Dendrogram of ESSTs. A split is seen between accessible (red) and inaccessible (blue) environments. Tail-layer environments (T**) appear not to cluster. Note that here, as elsewhere, ‘NPa’ and ‘NPA’ refer to combined +ve ϕ environments that include residues in the transmembrane regions (see Section 3.2).

Mentions: The Euclidean distance between the log-odds tables is used to create a ‘family-tree’ of the different environments (Figure 3). Tables for soluble proteins, labelled with a leading ‘s’, are included for comparison. When calculating the distance, each substitution is normalized by its standard deviation across all the tables. This prevents the distance measure being dominated by a handful of extreme substitution changes.Fig. 3.


Environment specific substitution tables improve membrane protein alignment.

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

Dendrogram of ESSTs. A split is seen between accessible (red) and inaccessible (blue) environments. Tail-layer environments (T**) appear not to cluster. Note that here, as elsewhere, ‘NPa’ and ‘NPA’ refer to combined +ve ϕ environments that include residues in the transmembrane regions (see Section 3.2).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 3: Dendrogram of ESSTs. A split is seen between accessible (red) and inaccessible (blue) environments. Tail-layer environments (T**) appear not to cluster. Note that here, as elsewhere, ‘NPa’ and ‘NPA’ refer to combined +ve ϕ environments that include residues in the transmembrane regions (see Section 3.2).
Mentions: The Euclidean distance between the log-odds tables is used to create a ‘family-tree’ of the different environments (Figure 3). Tables for soluble proteins, labelled with a leading ‘s’, are included for comparison. When calculating the distance, each substitution is normalized by its standard deviation across all the tables. This prevents the distance measure being dominated by a handful of extreme substitution changes.Fig. 3.

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