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Sequence-based prediction of protein binding mode landscapes

Fig 5

A binding mode landscape for disordered protein interactions.

Residues are characterised by their binding modes to increase or decrease order upon interactions and the context-dependence of such binding modes. (A) The binding modes, reflecting the level of disorder in the bound state, are represented on the x axis; ranging from structured, well-defined to disordered, heterogeneous interactions, as quantified by the p_DD values. Context-dependence, reflecting the level of fuzziness, is displayed on the y axis, ranging from stable, uniform to diverse, inducible binding modes, as quantified by the values. The p_DD and values are predicted from the sequence by the FuzPred program. A disorder-to-order binding with low context-dependence is exemplified by a disordered loop (504–512 aa, blue squares) in Taq polymerase, which adopts a stable structure upon interacting with DNA (PDB: 3lwl [54]). A disorder-to-disorder binding with low context-dependence is represented by the heterogeneous interactions between the elongation factor AF4 (residues 747–754, orange diamonds) with leukemia fusion protein AF9 (PDB:2lm0 [55]). Fuzzy, context-depedent interactions sample a wide variety of binding modes ranging from disorder-to-order to disorder-to-disorder transitions. Context-dependent disorder-to-order binding is exemplified by the polymorphic interactions of the ribosomal S6 kinase 1 (RSK1, residues 697–703, light blue dots), which adopts different secondary structures upon binding to S100B, corresponding to autoinhibited and active forms (PDB:5csf, 5csi, 5csj [23]). Conditional folding upon binding is represented by the N-terminal region (residues 15–25, lime dots) of the large chain of ribonucleoside-diphosphate reductase, which can be structured or disordered in different oligomers (PDB: 1zyz, 1zzd [56]). Context-dependent disordered binding is exemplified by the p150 subunit of the eukaryotic initiation factor 4F (residues 225–235, light orange dots). eIF4 wraps around the translation initiation factor 4E, but the flanking region remains to be highly dynamic in the assembly (PDB: 1rf8 [57]). The interaction sites are shown by the same colours as interaction modes, and partner proteins are displayed by grey surfaces. (B) The characteristics of the different binding modes, which are represented in panel A. The binding mode landscape comprises a continuum of interaction behaviours, the major trends of which are illustrated by the distinct modes.

doi: https://doi.org/10.1371/journal.pcbi.1007864.g005