Location of Repository

Contextual Specificity in Peptide-Mediated Protein Interactions

By Amelie Stein and Patrick Aloy

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

Topics: Research Article
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:2438476
Provided by: PubMed Central
Download PDF:
Sorry, we are unable to provide the full text but you may find it at the following location(s):
  • http://www.pubmedcentral.nih.g... (external link)
  • Suggested articles

    Preview

    Citations

    1. (1970). A general method applicable to the search for similarities in the amino acid sequence of two proteins.
    2. (2007). A genomewide Ras-effector interaction network.
    3. (2005). A human protein-protein interaction network: a resource for annotating the proteome.
    4. (2003). Assembly of cell regulatory systems through protein interaction domains.
    5. (2007). Cross-talk and decision making in MAP kinase pathways.
    6. (2002). Dissecting protein-protein recognition sites.
    7. (2002). domain of compartmentalized effector molecules.
    8. (2000). Dual epitope recognition by the VASP EVH1 domain modulates polyproline ligand specificity and binding affinity.
    9. (2003). ELM server: A new resource for investigating short functional sites in modular eukaryotic proteins.
    10. (2005). FHA domain-ligand interactions: importance of integrating chemical and biological approaches.
    11. Grishin NV (2001) AL2CO: calculation of positional conservation in a protein sequence alignment.
    12. (2005). Highthroughput mapping of a dynamic signaling network in mammalian cells.
    13. (1996). Inferring phylogenies from protein sequences by parsimony, distance, and likelihood methods.
    14. (2002). Interrogating protein interaction networks through structural biology.
    15. (2002). Intrinsically unstructured proteins.
    16. (2000). Ligand-protein interactions in nuclear receptors of hormones.
    17. (1992). Multiple protein sequence alignment from tertiary structure comparison: assignment of global and residue confidence levels.
    18. (2003). Optimization of specificity in a cellular protein interaction network by negative selection.
    19. (2007). Pathway redundancy and protein essentiality revealed in the Saccharomyces cerevisiae interaction networks.
    20. (2007). PDZ domain binding selectivity is optimized across the mouse proteome.
    21. (2006). Peptides mediating interaction networks: new leads at last.
    22. (2006). Pfam: clans, web tools and services.
    23. (2002). Predicting changes in the stability of proteins and protein complexes: a study of more than 1000 mutations.
    24. (2004). Protein interaction networks by proteome peptide scanning.
    25. (2005). Recognizing and defining true Ras binding domains II: in silico prediction based on homology modelling and energy calculations.
    26. RomeroPR,Zaidi S,FangYY,UverskyVN,RadivojacP,etal.(2006) Alternative splicing in concert with protein intrinsic disorder enables increased functional diversity in multicellular organisms.
    27. (1995). SCOP: a structural classification of proteins database for the investigation of sequences and structures.
    28. (2005). Sequential phosphorylation and multisite interactions characterize specific target recognition by the FHA domain of Ki67.
    29. (2005). Specificity and versatility of SH3 and other proline-recognition domains: structural basis and implications for cellular signal transduction.
    30. (2001). Structural basis for the inactivation of retinoblastoma tumor suppressor by SV40 large T antigen.
    31. (2004). Structural basis of protein phosphatase 1 regulation.
    32. (2006). Structural systems biology: modelling protein interactions.
    33. (1998). Structure and specificity of nuclear receptor-coactivator interactions.
    34. (2007). Systematic discovery of in vivo phosphorylation networks.
    35. (2005). Systematic interpretation of genetic interactions using protein networks.
    36. (2005). The FoldX web server: an online force field.
    37. (2000). The molecular basis of FHA domain:phosphopeptide binding specificity and implications for phospho-dependent signaling mechanisms.
    38. (1998). The nuclear receptor ligand-binding domain: structure and function.
    39. (2000). The Protein Data Bank.
    40. (2007). The stability effects of protein mutations appear to be universally distributed.
    41. (1999). The structural basis for the recognition of diverse receptor sequences by TRAF2.
    42. (2007). The use of in vitro peptide binding profiles and in silico ligand-receptor interaction profiles to describe ligand-induced conformations of the retinoid X receptor alpha ligand-binding domain.
    43. (2005). Towards a proteome-scale map of the human protein-protein interaction network.

    To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.