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Contextual specificity in peptide-mediated protein interactions - PubMed

  • ️Tue Jan 01 2008

Contextual specificity in peptide-mediated protein interactions

Amelie Stein et al. PLoS One. 2008.

Abstract

Most biological processes are regulated through complex networks of transient protein interactions where a globular domain in one protein recognizes a linear peptide from another, creating a relatively small contact interface. Although sufficient to ensure binding, these linear motifs alone are usually too short to achieve the high specificity observed, and additional contacts are often encoded in the residues surrounding the motif (i.e. the context). Here, we systematically identified all instances of peptide-mediated protein interactions of known three-dimensional structure and used them to investigate the individual contribution of motif and context to the global binding energy. We found that, on average, the context is responsible for roughly 20% of the binding and plays a crucial role in determining interaction specificity, by either improving the affinity with the native partner or impeding non-native interactions. We also studied and quantified the topological and energetic variability of interaction interfaces, finding a much higher heterogeneity in the context residues than in the consensus binding motifs. Our analysis partially reveals the molecular mechanisms responsible for the dynamic nature of peptide-mediated interactions, and suggests a global evolutionary mechanism to maximise the binding specificity. Finally, we investigated the viability of non-native interactions and highlight cases of potential cross-reaction that might compensate for individual protein failure and establish backup circuits to increase the robustness of cell networks.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Example of contextual specificity.

Interaction between the human retinoblastoma protein (grey) and the Simian virus 40 large T antigen (rainbow) (PDB id 1gh6 [18]). The consensus binding motif [LI].C.[DE] is shown in surface representation, and context residues as sticks.

Figure 2
Figure 2. Representative structures for the different types of peptide-mediated protein interactions.

Globular domains as defined in Pfam are shown in grey and binding proteins in rainbow colours. Consensus binding motifs are always shown in surface representation.

Figure 3
Figure 3. Topological variation of peptides binding human SH3 domains.

One domain is shown for each of the two possible orientations of SH3-binding peptides, in surface representation. Native and non-native peptides for class I (pattern [RKY]xxPxxP, left) and class II (pattern PxxPx[KR], right) are shown as ribbons. Key residues are highlighted as sticks. The first and last highlighted residues delimit the motifs; everything N- and C-terminal of that, respectively, is context. Both domains have a similar orientation in the figure, so, as the peptides have opposite orientations, the N-termini of the class I peptides are on the left, while those of the class II peptides are on the right.

Figure 4
Figure 4. Topological variation of peptides binding human PDZ domains.

As in Figure 4, the domain is shown in surface representation, native and non-native motifs as ribbons, and key residues as sticks. The PDZ domain primarily binds C-termini of peptides. While the motif and particularly the key residues are fixed in the binding groove, the N-terminal context is much less restrained.

Figure 5
Figure 5. Peptide exchange results for human SH3 domains.

Upper heat maps show the topological distortion (left) and the energy variations (right) of all artificial (i.e. non-native) interaction pairs constructed between human SH3 domains and their ligand proteins, with respect to the native topologies and the average native binding energy, respectively. SH3-binding peptides 1–9 correspond to class I and 10–16 to Class II. The lower figure shows the energy contribution of motif and context, with respect to the native binding energies, for each individual residue in the native (n) and artificial (a) interactions, determined by in silico alanine scanning. Detailed information is provided for the consensus motifs.

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