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Cited by 17Machine Learning in BioinformaticsBacterial Genetics and BiotechnologyProtein Structure and Dynamics

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General features of transmembrane beta barrels from a large database

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Montezano, Daniel, Bernstein, Rebecca, Copeland, Matthew M., Slusky, Joanna S. G.·2023·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2220762120PMC PMC10629564

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Abstract

Large datasets contribute new insights to subjects formerly investigated by exemplars. We used coevolution data to create a large, high-quality database of transmembrane β-barrels (TMBB). By applying simple feature detection on generated evolutionary contact maps, our method (IsItABarrel) achieves 95.88% balanced accuracy when discriminating among protein classes. Moreover, comparison with IsItABarrel revealed a high rate of false positives in previous TMBB algorithms. In addition to being more accurate than previous datasets, our database (available online) contains 1,938,936 bacterial TMBB proteins from 38 phyla, respectively, 17 and 2.2 times larger than the previous sets TMBB-DB and OMPdb. We anticipate that due to its quality and size, the database will serve as a useful resource where high-quality TMBB sequence data are required. We found that TMBBs can be divided into 11 types, three of which have not been previously reported. We find tremendous variance in proteome percentage among TMBB-containing organisms with some using 6.79% of their proteome for TMBBs and others using as little as 0.27% of their proteome. The distribution of the lengths of the TMBBs is suggestive of previously hypothesized duplication events. In addition, we find that the C-terminal β-signal varies among different classes of bacteria though its consensus sequence is LGLGYRF. However, this β-signal is only characteristic of prototypical TMBBs. The ten non-prototypical barrel types have other C-terminal motifs, and it remains to be determined if these alternative motifs facilitate TMBB insertion or perform any other signaling function.

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Fig. 1. The IsItABarrel algorithm. (A and B) Structures are colored from N to C terminus using rainbows from blue to red. Probability of contact is indicated by pixel gray value, with darker pixel indicating stronger contact between residues in x and y axis. (A) OmpT (PDB ID: 1I78) (Left) and corresponding contact map predicted by RaptorX-Contact (Right). The map shows typical features of β-barrel proteins, antiparallel contacts between neighboring strands (green circle) and the closing contact between the first and last strands of the barrel (purple circle). (B) Structure of the non-TMBB armadillo-repeat protein (PDB ID: 4V3O) (Left) and corresponding contact map predicted by RaptorX-Contact (Right) without the typical features found in maps of β-barrels. (C) Strand–strand interaction (β-hairpin) detection. Map is scanned along the main diagonal in search of β-hairpins. Detected β-hairpins are characterized in terms of the length of their contact network (Inset). The sum of the contact probabilities along a successfully detected β-hairpin is compared against the threshold for inclusion in the final TMBB classification step. (D) A closing contacts line is detected that aligns with the first and last strands. (E) Classification by IsItABarrel is a two-step process requiring either a closing contact or four hairpins. (F) Sequences sharing more than 40% identity tend to have the same IsItABarrel classification. Percentage of pairs that share the same IsItABarrel prediction (y axis) for each bin of percent similarity (x axis) (purple), total number of comparisons (log10) at each similarity level (gray). Dashed line at 40% pairwise sequence similarity. (G) Steps the algorithm used to assign IsItABarrel predictions by similarity. A large set of sequences is clustered by sequence similarity. IsItABarrel predictions are made for the cluster representatives. Cluster members are assigned the same prediction as their cluster representative.
Fig. 1. The IsItABarrel algorithm. (A and B) Structures are colored from N to C terminus using rainbows from blue to red. Probability of contact is indicated by pixel gray value, with darker pixel indicating stronger contact between residues in x and y axis. (A) OmpT (PDB ID: 1I78) (Left) and corresponding contact map predicted by RaptorX-Contact (Right). The map shows typical features of β-barrel proteins, antiparallel contacts between neighboring strands (green circle) and the closing contact between the first and last strands of the barrel (purple circle). (B) Structure of the non-TMBB armadillo-repeat protein (PDB ID: 4V3O) (Left) and corresponding contact map predicted by RaptorX-Contact (Right) without the typical features found in maps of β-barrels. (C) Strand–strand interaction (β-hairpin) detection. Map is scanned along the main diagonal in search of β-hairpins. Detected β-hairpins are characterized in terms of the length of their contact network (Inset). The sum of the contact probabilities along a successfully detected β-hairpin is compared against the threshold for inclusion in the final TMBB classification step. (D) A closing contacts line is detected that aligns with the first and last strands. (E) Classification by IsItABarrel is a two-step process requiring either a closing contact or four hairpins. (F) Sequences sharing more than 40% identity tend to have the same IsItABarrel classification. Percentage of pairs that share the same IsItABarrel prediction (y axis) for each bin of percent similarity (x axis) (purple), total number of comparisons (log10) at each similarity level (gray). Dashed line at 40% pairwise sequence similarity. (G) Steps the algorithm used to assign IsItABarrel predictions by similarity. A large set of sequences is clustered by sequence similarity. IsItABarrel predictions are made for the cluster representatives. Cluster members are assigned the same prediction as their cluster representative.CC BY-NC-ND · PubMed Central
Fig. 2. TMBB content in bacterial proteomes and signal peptide prevalence among organisms. Colored by class/phylum, categories are sorted by decreasing median number of TMBBs. (A) Distribution of number of TMBBs in 2,959 reference and representative bacterial proteomes. TMBBs predicted with IsItABarrel that were within other datasets (gray), and updated numbers after a full search with IsItABarrel (color). Number of TMBB proteins per organism by class/phylum (boxplot), fold increase in number of TMBBs from the initial search (stars using log10 scale at right). (B) Distribution of percentage of proteome predicted to encode TMBB proteins (same organisms as in A). (C) Percent of TMBBs with signal peptide detected by SignalP 5.0 for each organism, grouped by class/phylum.
Fig. 2. TMBB content in bacterial proteomes and signal peptide prevalence among organisms. Colored by class/phylum, categories are sorted by decreasing median number of TMBBs. (A) Distribution of number of TMBBs in 2,959 reference and representative bacterial proteomes. TMBBs predicted with IsItABarrel that were within other datasets (gray), and updated numbers after a full search with IsItABarrel (color). Number of TMBB proteins per organism by class/phylum (boxplot), fold increase in number of TMBBs from the initial search (stars using log10 scale at right). (B) Distribution of percentage of proteome predicted to encode TMBB proteins (same organisms as in A). (C) Percent of TMBBs with signal peptide detected by SignalP 5.0 for each organism, grouped by class/phylum.CC BY-NC-ND · PubMed Central
Fig. 3. Analysis of IsItABarrelDB by protein type. (A) Distribution of sequence lengths (dashed lines) and barrel lengths (solid lines) of the eleven largest types of TMBBs in the IsItABarrelDB. Number of TMBBs used to calculate sequence and barrel lengths in parenthesis. Maxima of the barrel sizes are labeled. (B) Correlation between barrel size for structurally resolved barrels and barrel size estimated by IsItABarrel using the closing contact feature. (C) Kernel density estimate of the distribution of sequence lengths for structurally resolved (gray) and IsItABarrelDB (black) TMBBs, rug plot showing instances below. (D) C-terminal sequence motifs found by MEME. Logo plots of motifs found in the C terminus of TMBBs for each protein type. The letters at each position are ordered from top to bottom by most common to least common. The height of each letter is proportional to its frequency in the column, while the height of the stack is adjusted to be the information content expressed in bits of the aligned sequences at that particular position. The colors of the letters indicate physicochemical properties: orange–small, magenta–acidic, blue–hydrophobic plus cysteine, cyan–tyrosine, pink–histidine, green–polar, red–basic, yellow–proline. The number of TMBBs used for the search is at top in parenthesis.
Fig. 3. Analysis of IsItABarrelDB by protein type. (A) Distribution of sequence lengths (dashed lines) and barrel lengths (solid lines) of the eleven largest types of TMBBs in the IsItABarrelDB. Number of TMBBs used to calculate sequence and barrel lengths in parenthesis. Maxima of the barrel sizes are labeled. (B) Correlation between barrel size for structurally resolved barrels and barrel size estimated by IsItABarrel using the closing contact feature. (C) Kernel density estimate of the distribution of sequence lengths for structurally resolved (gray) and IsItABarrelDB (black) TMBBs, rug plot showing instances below. (D) C-terminal sequence motifs found by MEME. Logo plots of motifs found in the C terminus of TMBBs for each protein type. The letters at each position are ordered from top to bottom by most common to least common. The height of each letter is proportional to its frequency in the column, while the height of the stack is adjusted to be the information content expressed in bits of the aligned sequences at that particular position. The colors of the letters indicate physicochemical properties: orange–small, magenta–acidic, blue–hydrophobic plus cysteine, cyan–tyrosine, pink–histidine, green–polar, red–basic, yellow–proline. The number of TMBBs used for the search is at top in parenthesis.CC BY-NC-ND · PubMed Central
Fig. 4. Analysis of IsItABarrelDB by phylum. (A) The distribution of the eleven protein types and unclassified IsItABarrelDB TMBB sequences among 38 phyla. A red to blue scale indicates greater to fewer numbers of that protein type or no proteins of that type (white). Phyla are organized by Terrabacteria and Gracilicutes (gray and black dots, lowest row), and colored dots that show clades within those categories (middle row), clades are as previously described (48, 49) FCB–Fibrobacteres/Chlorobi/Bacteroidetes, PANNAM–Proteobacteria/Acidobacteria/Nitrospinae/Nitrospirae/Aminicenantes/Methylomirabilis, PVC–Planctomycetes/Verrucomicrobia/Chlamydiae, DST–Deinococcus-Thermus/Synergistetes/Thermotogae, CCD–CPR/Chloroflexi/Dormibacteraeota, CMS–Cyanobacteria/Melainabacteria/Margulisbacteria-Saganbacteria. Dots are also used to indicate the presence of a classic β-signal (top row, red, and green). The Unclassified type across all phyla includes 274,245 sequences. (B) Sequence logos of the prototypical β-signal of each phyla that has a clear traditional β-signal. Logos as described in Fig. 2D. No logo plot was created for Atribacterota because it only contained two proteins.
Fig. 4. Analysis of IsItABarrelDB by phylum. (A) The distribution of the eleven protein types and unclassified IsItABarrelDB TMBB sequences among 38 phyla. A red to blue scale indicates greater to fewer numbers of that protein type or no proteins of that type (white). Phyla are organized by Terrabacteria and Gracilicutes (gray and black dots, lowest row), and colored dots that show clades within those categories (middle row), clades are as previously described (48, 49) FCB–Fibrobacteres/Chlorobi/Bacteroidetes, PANNAM–Proteobacteria/Acidobacteria/Nitrospinae/Nitrospirae/Aminicenantes/Methylomirabilis, PVC–Planctomycetes/Verrucomicrobia/Chlamydiae, DST–Deinococcus-Thermus/Synergistetes/Thermotogae, CCD–CPR/Chloroflexi/Dormibacteraeota, CMS–Cyanobacteria/Melainabacteria/Margulisbacteria-Saganbacteria. Dots are also used to indicate the presence of a classic β-signal (top row, red, and green). The Unclassified type across all phyla includes 274,245 sequences. (B) Sequence logos of the prototypical β-signal of each phyla that has a clear traditional β-signal. Logos as described in Fig. 2D. No logo plot was created for Atribacterota because it only contained two proteins.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Montezano, D., Bernstein, R., Copeland, M. M., & Slusky, J. S. G.
Affiliations
University of Kansas (US)
Corresponding author
Slusky, Joanna S. G.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2023-07-11
Volume
120
Issue
29
Pages
e2220762120-e2220762120
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.2220762120
PMC
PMC10629564
OpenAlex
W4383874614
Cited by
17
References
4
Citations by year
2026: 8 · 2025: 3 · 2024: 6
FWCI
1.51
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
Funders
  • HHS | NIH | National Institute of General Medical Sciences (DP2 GM128201, P20GM103418)
  • National Science Foundation (2226804)
  • American-Scandinavian Foundation (Fellowship)
  • KU | Office of Research, University of Kansas (Startup)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Machine Learning in Bioinformatics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
transmembrane beta-barrel, bacterial membrane proteins, protein coevolution, protein databases, proteome composition
MeSH terms
Algorithms, Bacterial Proteins, Biological Evolution, Humans, Consensus Sequence, Proteome

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Montezano, D., Bernstein, R., Copeland, M. M., & Slusky, J. S. G. (2023). General features of transmembrane beta barrels from a large database. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.2220762120