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Large-scale discovery of protein interactions at residue resolution using co-evolution calculated from genomic sequences
Open accessAbstract
Increasing numbers of protein interactions have been identified in high-throughput experiments, but only a small proportion have solved structures. Recently, sequence coevolution-based approaches have led to a breakthrough in predicting monomer protein structures and protein interaction interfaces. Here, we address the challenges of large-scale interaction prediction at residue resolution with a fast alignment concatenation method and a probabilistic score for the interaction of residues. Importantly, this method (EVcomplex2) is able to assess the likelihood of a protein interaction, as we show here applied to large-scale experimental datasets where the pairwise interactions are unknown. We predict 504 interactions de novo in the E. coli membrane proteome, including 243 that are newly discovered. While EVcomplex2 does not require available structures, coevolving residue pairs can be used to produce structural models of protein interactions, as done here for membrane complexes including the Flagellar Hook-Filament Junction and the Tol/Pal complex.
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![Fig. 2 Model predicts interacting residues and interacting proteins with high precision. A Recall on the held-out fraction of the positive benchmark set (x-axis) and false positive rate on the held-out dataset of non-interacting complexes (y-axis) at a score threshold that gives the corresponding recall. Our logistic regression model (purple) reduces the false positive rate compared to the previous EV Complex score (blue). B Prediction of protein interaction is based on the prediction of interacting residues. Number of predicted interacting residue pairs for complexes inferred to interact (purple) or not inferred to interact (gray) based on our stringent protein complex prediction threshold. C Example performance on known interaction between ABC transporter permease and ATP binding subunit (UniProt IDs: Y1470_HAEIN and Y1471_HAEIN, PDB ID: 2NQ2 chains C and A [https://www.rcsb.org/structure/2NQ2]. D Example performance on known interaction between DNA primase PriS and PriL (UniProt IDs: PRIS_SULSO and PRIL_SULSO, PDB ID: 1ZT2 chain A and B [https://www.rcsb.org/structure/1ZT2]).](/paper-figures/8c99d2bf4a504b23915ac20b65474882/large-scale-discovery-of-protein-interactions-at-residue-resolution-using-co-figure-2.jpg)
![Fig. 3 Discovery of hundreds of new interactions in the E. coli membrane proteome. A We searched a high-value subset of the 10∧7 possible interactions in the E. coli proteome by searching membrane compartments with themselves and with adjacent membrane compartments. B We found 504 high-scoring protein interactions in the cell envelope, including 75 with structural characterization and 186 with previous experimental evidence (and no structural characterization). C–E 3D configurations of previously structurally characterized interactions are accurately predicted by molecular docking with inferred restraints. RMSDs calculated by comparison to known structures with PDB IDs 3RKO [https://www.rcsb.org/structure/3RKO], 2WU2 [https://www.rcsb.org/structure/2WU2], and 2HQS [https://www.rcsb.org/structure/2HQS], respectively. F–H Example of three docked models of newly resolved protein complexes: BamE/MltB, YajC/FtsI, and Lnt/MurJ. Evolutionarily coupled residues used as restraints in docking are shown in magenta and connected with solid lines.](/paper-figures/4a6f05b9624e471291ece061750a4d89/large-scale-discovery-of-protein-interactions-at-residue-resolution-using-co-figure-3.jpg)
![Fig. 4 Model of the flagellar hook-filament junction. A Schematic of the orientation of the bacterial flagellum. The proteins FlgL (green) and FlgK (blue) form two rings which create the junction between the hook and filament of the flagellum24. B Docked model of FlgL and FlgK using evolutionary couplings. PDB structures of homologous proteins from Salmonella typhimurium were used in docking (PDB IDs 2D4Y [https://www.rcsb.org/structure/2D4Y], and 2D4X [https://www.rcsb.org/structure/2D4X], respectively). Predicted interface residues are highlighted in purple. C A previously inferred model of the FlgK ring from Campylobacter jejuni24 was used to infer the structure of the entire hook-filament junction. Evolutionary coupled residues (purple) show the interface for FlgL ring insertion into the FlgK ring. By aligning our docked model to the C. jejuni ring, we show that an 11-mer ring of FlgL fits inside the FlgK structure.](/paper-figures/2f04c515d1b4411fa5d72558ae1a1263/large-scale-discovery-of-protein-interactions-at-residue-resolution-using-co-figure-4.jpg)
![Fig. 5 Atomic resolution model of the Tol-Pal complex. A Schematic of the proteins involved in the Tol-Pal complex2 (TolABR, CpoB, and Pal). Interactions with previously solved interfaces are shown in orange and interactions inferred by our method are shown in purple. B Complete model of the Tol-Pal complex inferred by aligning results of docked pairwise models. Note that CpoB is inferred to be a trimer in vivo but was docked as a monomer for modeling purposes C–F Residue resolution of TolB-Pal, TolB-TolA, TolR-TolB, and CpoB-TolB interfaces. The top 5 inferred interface contacts are shown in purple. Dashed lines indicate inferred contacts where one or more residues are missing from the solved structure. Structures used are 1TOL_A (TolA) [https://www.rcsb.org/structure/1TOL], 2HQS_A (TolB) [https://www.rcsb.org/structure/2HQS], 5BY4_A (TolR) [https://www.rcsb.org/structure/5BY4], 2HQS_H (Pal) [https://www.rcsb.org/structure/2HQS], and 2XDJ_A (CpoB) [https://www.rcsb.org/structure/2XDJ].](/paper-figures/4aeb569056cf42b881376a4f19038abe/large-scale-discovery-of-protein-interactions-at-residue-resolution-using-co-figure-5.jpg)
![Fig. 6 Predicted protein interactions in eukaryotic proteomes. A Distribution of eukaryotic sequences in concatenated sequence alignments. Shown in orange are alignments that passed our sequence diversity threshold, and in gray are those that did not. B Number of correctly predicted inter-protein ECs for eukaryotic-exclusive complexes above the sequence diversity threshold. Eukaryotic-exclusive complexes are defined as complexes whose concatenated sequence alignment is at least 90% eukaryotic sequences. Inter protein ECs are defined as correct if their minimum atom distance is <8 Å. C The human spliceosome proteins Prp38 and MFAP1 have a known interface correctly predicted by our method, and have a protein interaction detected. The inter-protein ECs above the 80% precision threshold used throughout the paper are shown in purple. Known protein structure (PDB ID: 5F5U, [https://www.rcsb.org/structure/5F5U]) is used to visualize the subunits. D Schematic of predicted interaction between Lsm5 and Prp38 with top 5 inter-protein ECs.](/paper-figures/72ac0543df0e4718b992c18782b93f63/large-scale-discovery-of-protein-interactions-at-residue-resolution-using-co-figure-6.jpg)
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“Because residues at protein-protein interfaces are expected to coevolve, the likelihood that any two proteins interact can be assessed by identifying and aligning the ortholog sequences of the two proteins in many different species, joining them to create paired multiple sequence alignments (pMSA), and then determining the extent to which changes in the sequences of orthologs for the first protein”
From Computed structures of core eukaryotic protein complexes (2021) · cites this paper as [10]
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Metadata
- Authors
- Green, A. G., Elhabashy, H., Brock, K. P., Maddamsetti, R., Kohlbacher, O., & Marks, D. S.
- Affiliations
- Harvard University (US)
- Max Planck Institute for Developmental Biology (DE)
- Universitätsklinikum Tübingen (DE)
- Broad Institute (US)
- Corresponding author
- Kohlbacher, Oliver
- Marks, Debora S.
- ORCID
- Venue
- Nature Communications
- Published
- 2021-03-02
- Volume
- 12
- Issue
- 1
- Pages
- 1396-1396
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC7925567
- OpenAlex
- W3133793061
- Cited by
- 114
- References
- 57
- Citations by year
- 2026: 14 · 2025: 17 · 2024: 24 · 2023: 25 · 2022: 21 · 2021: 13
- FWCI
- 6.51
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Science Foundation (DGE1144152)
- U.S. Department of Health & Human Services | National Institutes of Health (T15LM007092)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Machine Learning in Bioinformatics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Keywords
- protein-protein interaction, membrane protein complexes
- MeSH terms
- Amino Acids, Bacterial Proteins, Base Sequence, Escherichia coli, Eukaryotic Cells, Membrane Proteins, Protein Binding, Genome, Bacterial, Evolution, Molecular, Proteome, Protein Interaction Mapping, Molecular Docking Simulation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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