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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

Box plots of the fraction of residues aligned correctly as sequence identity increases. There are three boxes at each sequence identity, from left to right corresponding to membrane FUGUE (black), default FUGUE (blue) and MUSCLE (red). The green bars show the number of alignments divided by 100. For example, there are 78 alignments in the 5–10% sequence identity range.
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Figure 5: Box plots of the fraction of residues aligned correctly as sequence identity increases. There are three boxes at each sequence identity, from left to right corresponding to membrane FUGUE (black), default FUGUE (blue) and MUSCLE (red). The green bars show the number of alignments divided by 100. For example, there are 78 alignments in the 5–10% sequence identity range.

Mentions: Alignments were made for the remaining 336 pairs of proteins in the alignment dataset. None of the methods performed well in the 0–10% sequence identity range, but beyond this the membrane tables gave a consistent alignment advantage. At >35% sequence identity, the alignments show few differences. Figure 5 compares the alignments of membrane specific tables to common alternatives. PHAT/BLOSUM62 is omitted for clarity—its performance is comparable to that of default FUGUE.Fig. 5.


Environment specific substitution tables improve membrane protein alignment.

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

Box plots of the fraction of residues aligned correctly as sequence identity increases. There are three boxes at each sequence identity, from left to right corresponding to membrane FUGUE (black), default FUGUE (blue) and MUSCLE (red). The green bars show the number of alignments divided by 100. For example, there are 78 alignments in the 5–10% sequence identity range.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 5: Box plots of the fraction of residues aligned correctly as sequence identity increases. There are three boxes at each sequence identity, from left to right corresponding to membrane FUGUE (black), default FUGUE (blue) and MUSCLE (red). The green bars show the number of alignments divided by 100. For example, there are 78 alignments in the 5–10% sequence identity range.
Mentions: Alignments were made for the remaining 336 pairs of proteins in the alignment dataset. None of the methods performed well in the 0–10% sequence identity range, but beyond this the membrane tables gave a consistent alignment advantage. At >35% sequence identity, the alignments show few differences. Figure 5 compares the alignments of membrane specific tables to common alternatives. PHAT/BLOSUM62 is omitted for clarity—its performance is comparable to that of default FUGUE.Fig. 5.

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