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. 2020 Dec;16(12):e9310.
doi: 10.15252/msb.20199310.

Large-scale survey and database of high affinity ligands for peptide recognition modules

Joan Teyra  1 , Abdellali Kelil  1 , Shobhit Jain  1   2 , Mohamed Helmy  1 , Raghav Jajodia  3 , Yogesh Hooda  1 , Jun Gu  1 , Akshay A D'Cruz  4 , Sandra E Nicholson  4 , Jinrong Min  5   6 , Marius Sudol  7 , Philip M Kim  1   2   8 , Gary D Bader  1   2   8 , Sachdev S Sidhu  1   8
Affiliations

Large-scale survey and database of high affinity ligands for peptide recognition modules

Joan Teyra et al. Mol Syst Biol. 2020 Dec.

Abstract

Many proteins involved in signal transduction contain peptide recognition modules (PRMs) that recognize short linear motifs (SLiMs) within their interaction partners. Here, we used large-scale peptide-phage display methods to derive optimal ligands for 163 unique PRMs representing 79 distinct structural families. We combined the new data with previous data that we collected for the large SH3, PDZ, and WW domain families to assemble a database containing 7,984 unique peptide ligands for 500 PRMs representing 82 structural families. For 74 PRMs, we acquired enough new data to map the specificity profiles in detail and derived position weight matrices and binding specificity logos based on multiple peptide ligands. These analyses showed that optimal peptide ligands resembled peptides observed in existing structures of PRM-ligand complexes, indicating that a large majority of the phage-derived peptides are likely to target natural peptide-binding sites and could thus act as inhibitors of natural protein-protein interactions. The complete dataset has been assembled in an online database (http://www.prm-db.org) that will enable many structural, functional, and biological studies of PRMs and SLiMs.

Keywords: domain specificity; peptide inhibitors; peptide library; peptide recognition modules; phage display.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1. Specificity profiles for PRMs
The specificity profiles for 74 PRMs are represented as logos showing the preferences at each peptide position. The following information is provided above each logo: name of the protein from which the PRM was derived, PRM family name, number of peptide sequences used to derive the logo (seq), and total specificity potential score (SPt) for the logo. Logos are presented in alphabetical order by family.
Figure 2
Figure 2. Physicochemical properties of PRM ligands
Data are shown for the 74 PRMs for which specificity profiles were determined in this study (new PRMs, Fig 1), for human SH3, PDZ and WW domains studied previously (Tonikian et al, 2008; Teyra et al, 2017), and for SLiMs and disorderome peptides.

  1. Distribution of specificity profile lengths.

  2. Distribution of total specificity potential (SPt) scores.

  3. Frequencies of amino acids at specific and non‐specific positions in phage‐derived peptides and SLiMs, and in disorderome peptides. Amino acids are ordered from highest to lowest hydrophobicity measured by Roseman’s Hydropathy Index (RHI), which is shown below each amino acid denoted by the single‐letter code.

  4. Distribution of the RHI for specific and non‐specific positions in phage‐derived peptides and SLiMs and in disorderome peptides.

Figure 3
Figure 3. Comparison of PRMs and phage‐derived ligands with matched PRM‐ligand complex structures
Data are shown for 135 of 163 PRMs that yielded at least one phage‐derived ligand and for which the PDB contained at least one PRM with > 10% sequence identity, and these are compared with the best‐matched PRM/ligand complex in the PDB (Dataset EV5).

  1. Distribution of sequence identities between the studied PRMs and the matched PRM structures for the full sequence or the sequence of the peptide‐binding interface region.

  2. Distribution of sequence similarities between the ligand in the complex structure and the most similar phage‐derived peptide for all 135 PRMs.

  3. Distribution of sequence similarities between the ligand in the complex structure and the most similar phage‐derived peptide for the 63 PRMs with specificity profiles (Fig 1), either at specific positions or non‐specific positions.

  4. Distribution of sequence similarities between the ligand in the complex structure and the most similar phage‐derived peptide at contact and non‐contact positions in the structure.

Figure 4
Figure 4. Comparison of phage‐derived ligands and structures of peptides in complex with PRMs
Depicted are the 55 PRMs for which phage‐derived specificity profiles were determined (Fig 1) and for which the structure peptide did not contain a PTM. The name of the protein from which the studied PRM was derived is listed at the top with the PRM family name in parenthesis, followed by the specificity profile logo determined from phage‐derived peptides, and sorted alphabetically by family. The alignment below the logo shows the sequences of a phage‐derived peptide (top) and the peptide ligand from the best‐matched PRM‐ligand complex structure in the PDB (bottom). Similar residues in the two peptides are shaded gray and residues that make contact with the PRM in the structure are underlined. The structure of the best‐matched PRM‐ligand complex in the PDB is shown with the PRM and peptide ligand main chains rendered as gray or green ribbons, respectively. Red and blue spheres denote ligand positions that are similar to the phage‐derived peptide and are contact or non‐contact positions, respectively. The peptide main chain is only depicted for those residues that are shown in the alignment with the phage‐derived peptide. The PDB entry code is shown above each structure.
Figure 5
Figure 5. Comparison of phage‐derived ligands and structures of PTM‐containing peptides in complex with PRMs
  1. A–C

    Depicted are the 17 PRMs for which the ligand in the structure contains (A) pSer/pThr, (B) pTyr, or (C) meArg/meLys. The name of the protein from which the studied PRM was derived is listed at the top with the PRM family name in parenthesis, followed by the specificity profile determined from phage‐derived peptides, if available. Below, the alignment shows the sequences of a phage‐derived peptide (top) and the peptide ligand from the best‐matched PRM‐ligand complex in the PDB (bottom). Similar residues in the two peptides are shaded gray and residues that make contact with the PRM in the structure are underlined. Filled circles below the alignment indicate residues that contain PTMs. The structure of the best‐matched PRM‐ligand complex from the PDB is shown with the PRM and peptide ligand main chains rendered as gray or green ribbons, respectively. Red and blue spheres denote ligand positions that are similar to the phage‐derived peptide and are contact or non‐contact positions, respectively. Side chains that contain PTMs are shown as yellow sticks. The peptide main chain is only depicted for those residues that are shown in the alignment with the phage‐derived peptide. The PDB entry code is shown above each structure.

Figure 6
Figure 6. Comparison of phage‐derived ligands and natural SLiMs in complex with PRMs
Depicted are eight PRMs for which phage‐derived specificity profiles were determined (Fig 1) and for which natural SLiM ligand information is available in the ELM repository (Dataset EV6). The name of the protein from which the studied PRM was derived is listed at the top with the PRM family name in parenthesis. The box shows a close‐up of the structure of the peptide‐binding site of the PRM, which is depicted as a gray surface (the PDB entry code is shown in the bottom right corner). The peptide ligand is colored green with the main chain shown as a tube and side chains shown as sticks (the N terminus is to the left), and its sequence is shown directly below the structure in bold text. Below the peptide ligand sequence, the following are shown: the phage‐derived specificity profile, the phage‐derived peptide most similar to the ELM motif, and the ELM motif (below the horizontal line). Sequences in the peptide structure, the peptide ligand, and the phage‐derived peptide that match the ELM motif are shaded gray. The ELM motifs are arranged vertically to align with the specificity profile and peptides. Position allowing any amino acid except Pro is depicted as “P” crossed out with a diagonal line.
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References

    1. Betts MJ, Russell RB (2003) Amino acid properties and consequences of substitutions Bioinformatics for geneticists, pp 289–316. John Wiley & Sons, Ltd;
    1. Carducci M, Perfetto L, Briganti L, Paoluzi S, Costa S, Zerweck J, Schutkowski M, Castagnoli L, Cesareni G (2012) The protein interaction network mediated by human SH3 domains. Biotechnol Adv 30: 4–15 - PubMed
    1. Chatr‐aryamontri Andrew, Oughtred Rose, Boucher Lorrie, Rust Jennifer, Chang Christie, Kolas Nadine K, O'Donnell Lara, Oster Sara, Theesfeld Chandra, Sellam Adnane, Stark Chris, Breitkreutz Bobby‐Joe, Dolinski Kara, Tyers Mike (2017) The BioGRID interaction database: 2017 update. Nucleic Acids Res 45: D369–D379 - PMC - PubMed
    1. Chen G, Gorelik L, Simon KJ, Pavlenco A, Cheung A, Brickelmaier M, Chen LL, Jin P, Weinreb PH, Sidhu SS (2015) Synthetic antibodies and peptides recognizing progressive multifocal leukoencephalopathy‐specific point mutations in polyomavirus JC capsid viral protein 1. mAbs 7: 681–692 - PMC - PubMed
    1. Davey NE, Van Roey K, Weatheritt RJ, Toedt G, Uyar B, Altenberg B, Budd A, Diella F, Dinkel H, Gibson TJ (2012) Attributes of short linear motifs. Mol BioSyst 8: 268–281 - PubMed

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