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Comparative Study
. 2008;9 Suppl 1(Suppl 1):S1.
doi: 10.1186/1471-2164-9-S1-S1.

Flexible nets: disorder and induced fit in the associations of p53 and 14-3-3 with their partners

Christopher J Oldfield  1 , Jingwei Meng, Jack Y Yang, Mary Qu Yang, Vladimir N Uversky, A Keith Dunker
Affiliations
Comparative Study

Flexible nets: disorder and induced fit in the associations of p53 and 14-3-3 with their partners

Christopher J Oldfield et al. BMC Genomics. 2008.

Abstract

Background: Proteins are involved in many interactions with other proteins leading to networks that regulate and control a wide variety of physiological processes. Some of these proteins, called hub proteins or hubs, bind to many different protein partners. Protein intrinsic disorder, via diversity arising from structural plasticity or flexibility, provide a means for hubs to associate with many partners (Dunker AK, Cortese MS, Romero P, Iakoucheva LM, Uversky VN: Flexible Nets: The roles of intrinsic disorder in protein interaction networks. FEBS J 2005, 272:5129-5148).

Results: Here we present a detailed examination of two divergent examples: 1) p53, which uses different disordered regions to bind to different partners and which also has several individual disordered regions that each bind to multiple partners, and 2) 14-3-3, which is a structured protein that associates with many different intrinsically disordered partners. For both examples, three-dimensional structures of multiple complexes reveal that the flexibility and plasticity of intrinsically disordered protein regions as well as induced-fit changes in the structured regions are both important for binding diversity.

Conclusions: These data support the conjecture that hub proteins often utilize intrinsic disorder to bind to multiple partners and provide detailed information about induced fit in structured regions.

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Figures

Figure 1
Figure 1
Summary of p53 interactions and structure. Dark gray boxes indicate the approximate binding regions of p53's known binding partners. The regions of p53 represented in structure complexes in PDB are represented by horizontal bars, labeled with the name of the binding partner. For the DBD, the extent of the globular domain is indicated by the light grey box, where the internal horizontal bars indicate regions involved in binding to a particular partner. Post translational modifications sites are represented by vertical ticks. Experimentally characterized regions of disorder (red) and order (blue) are indicated by the horizontal bar. Finally, predictions of disorder (scores > 0.5) and order (scores < 0.5) are shown for two PONDR predictors: VLXT (solid line) and VSL2P (dashed line). All, features are presented to scale, as indicated by the horizontal axis. The p53 interaction partners and post translational modification sites have been adapted from Anderson & Appella [55].
Figure 2
Figure 2
Double NMA-NIA plot for p53 complexes. (A) The definition of boundary distance used in the double NMA-NIA plot, where ordered structures have a negative boundary distance and disordered structures have a positive boundary distance. (B) The double NMA-NIA plot for the p53 structures shown in Figure 1, with the exception of DNA-bound p53.
Figure 3
Figure 3
Sequence and structure comparison for the four overlapping complexes in the C-terminus of p53. (A) Primary, secondary, and quaternary structure of p53 complexes. (B) The ΔASA for rigid association between the components of complexes for each residue in the relevant sequence region of p53. The two hatched bars indicate acetylated lysine residues.
Figure 4
Figure 4
p53 DBD interaction with different binding partners. The interaction profiles (A) and rendered structures (B) for the four unique complexes of the p53 DBD. Rendered structures depict p53 as a ribbon and each interaction partner as a molecular surface. The interaction profile-structure pairs are (from top to bottom): p53-DNA, p53-53BP1, p53-53BP2, and p53-sv40.
Figure 5
Figure 5
Comparison of residue interactions with structural differences for bound p53 DBD. The average (A) and standard deviations (B) were calculated over the four interaction profiles of the p53 DBD shown in Figure 4. These are shown aligned with the side chain RMSF (C) and the backbone RMSF (D) calculated from the four structures of bound p53 DBD. Regions of residues that are highly exposed to solvent in all complex structures are indicated by the blue-shaded regions.
Figure 6
Figure 6
Sequence and structure for five peptides bound to 14-3-3ζ. (A) Sequence alignment of the bound peptides and the RMSF of their conformations. Solid grey bars give the RMSF for four peptides – excluding R18 – and the hatched bars give the RMSF for all five peptides. (B) Aligned ribbon representations of the structures of the five peptides, which were aligned through multiple alignment of their respectively bound 14-3-3 domains, show along with a representative ribbon representation of a 14-3-3 domain.
Figure 7
Figure 7
Peptide binding residues of 14-3-3ζ. (A) The Cβ atoms of all residues involved in binding in any of the five peptide bound structures are shown (red) along with the rest of the backbone (light blue ribbon). (B) The standard deviation in the area bound on complex formation is displayed by coloring the Cβ atoms of peptide binding residues on a gradient, from a standard deviation of 0Å2 (blue) to 10Å2 and greater (red). (C) The backbone RMSF of the 14-3-3 domain calculated over Cα atoms displayed as a color and radius gradient, from an RMSF of 0Å (blue, 0.25Å) to an RMSF of 2.0Å and greater (red, 2.0Å). (D) The side chain RMSF is displayed by coloring the Cβ atoms of peptide binding residues on a gradient, from a RMSF of 0Å (blue) to an RMSF of 0.50Å and greater (red). All parameters were calculated using all five of the peptide-14-3-3 complexes.
Figure 8
Figure 8
Comparison of residue interactions with structural differences for bound 14-3-3ζ. The average (A) and standard deviations (B) were calculated over the five 14-3-3ζ-peptide interaction profiles. These are shown aligned with the side chain RMSF (C) and the backbone RMSF (D) calculated from the five structures of bound 14-3-3ζ. Regions of residues that are highly exposed to solvent in all complex structures are indicated by the blue-shaded regions.
Figure 9
Figure 9
Detailed analysis of 14-3-3ζ peptide binding. The m1 peptide (A, orange ribbon) and m2 peptide (B, red ribbon) bound to 14-3-3 (A and B, shown by the green and blue surface, respectively). Details of 14-3-3 peptide binding are shown by a chemical schematic for the m1 peptide (C) and the m2 peptide (D), where both crystallographic waters (blue) and implicit waters (red) are shown. (E) Superposition of the backbone atoms from the 4 helices with the primary peptide binding residues for m1 (green) and m2 (blue) bound 14-3-3. (F) Superposition of ribbons of the same 4 helices showing the side chains of the residues that participate in m1 (green) and/or m2 (blue) binding.
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