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Structural basis for ASPP2 recognition by the tumor suppressor p73.

Canning P, von Delft F, Bullock AN - J. Mol. Biol. (2012)

Bottom Line: The loop in p73 is changed by a two-residue insertion that also induces repacking around the site of the p53 mutational hotspot R175.Importantly, the binding of ASPP2 is preserved by conformational changes in both the ankyrin repeat and SH3 domains.These results further highlight the structural variation that impacts p53 family interactions within the p53 interactome.

View Article: PubMed Central - PubMed

Affiliation: Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK.

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Conserved ligand interactions with the RT loop. (a) Superposition of the p73–ASPP2 complex with a Cbl-b peptide bound to the SH3 domains of CIN85 (PDB ID 2BZ8).45 The surface of one CIN85 SH3 domain is shown in gray, and the Cbl-b and p73 chains are shown in red and green, respectively. The p73 L3 loop is structurally distinct from the extended proline-rich sequences of most SH3 ligands. (b) Although the binding mode of p73 is distinct from extended SH3 ligand interactions, several features are conserved. These include the critical arginine interaction with the RT loop and a backbone hydrogen bond to ASPP2 W1097.
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f0045: Conserved ligand interactions with the RT loop. (a) Superposition of the p73–ASPP2 complex with a Cbl-b peptide bound to the SH3 domains of CIN85 (PDB ID 2BZ8).45 The surface of one CIN85 SH3 domain is shown in gray, and the Cbl-b and p73 chains are shown in red and green, respectively. The p73 L3 loop is structurally distinct from the extended proline-rich sequences of most SH3 ligands. (b) Although the binding mode of p73 is distinct from extended SH3 ligand interactions, several features are conserved. These include the critical arginine interaction with the RT loop and a backbone hydrogen bond to ASPP2 W1097.

Mentions: The low micromolar affinity of the ASPP2 complexes remains in the normal range for SH3 domain interactions. Typical proline-rich ligands form backbone interactions across the SH3 surface, while an arginine residue orients their binding motif by interacting with the RT loop. Although the binding mode of p53 family members is distinct, interacting through two separate loop regions, several features are conserved (Fig. 8a). The RT loop interaction of p73 R268 shows a highly similar bonding configuration to Cbl-b R911 in complex with the endocytic regulator protein CIN85 (Fig. 8),45 although the backbone positions are quite different (Fig. 8b). The backbone hydrogen bond formed by p73 S261 is also analogous to the interaction of the P− 2 residue of classical SH3 binding motifs (Fig. 8b). The interaction between Cbl-b and CIN85 is itself unusual as the proline–arginine motif of Cbl-b spans across the multiple SH3 domains of CIN85.45


Structural basis for ASPP2 recognition by the tumor suppressor p73.

Canning P, von Delft F, Bullock AN - J. Mol. Biol. (2012)

Conserved ligand interactions with the RT loop. (a) Superposition of the p73–ASPP2 complex with a Cbl-b peptide bound to the SH3 domains of CIN85 (PDB ID 2BZ8).45 The surface of one CIN85 SH3 domain is shown in gray, and the Cbl-b and p73 chains are shown in red and green, respectively. The p73 L3 loop is structurally distinct from the extended proline-rich sequences of most SH3 ligands. (b) Although the binding mode of p73 is distinct from extended SH3 ligand interactions, several features are conserved. These include the critical arginine interaction with the RT loop and a backbone hydrogen bond to ASPP2 W1097.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3472557&req=5

f0045: Conserved ligand interactions with the RT loop. (a) Superposition of the p73–ASPP2 complex with a Cbl-b peptide bound to the SH3 domains of CIN85 (PDB ID 2BZ8).45 The surface of one CIN85 SH3 domain is shown in gray, and the Cbl-b and p73 chains are shown in red and green, respectively. The p73 L3 loop is structurally distinct from the extended proline-rich sequences of most SH3 ligands. (b) Although the binding mode of p73 is distinct from extended SH3 ligand interactions, several features are conserved. These include the critical arginine interaction with the RT loop and a backbone hydrogen bond to ASPP2 W1097.
Mentions: The low micromolar affinity of the ASPP2 complexes remains in the normal range for SH3 domain interactions. Typical proline-rich ligands form backbone interactions across the SH3 surface, while an arginine residue orients their binding motif by interacting with the RT loop. Although the binding mode of p53 family members is distinct, interacting through two separate loop regions, several features are conserved (Fig. 8a). The RT loop interaction of p73 R268 shows a highly similar bonding configuration to Cbl-b R911 in complex with the endocytic regulator protein CIN85 (Fig. 8),45 although the backbone positions are quite different (Fig. 8b). The backbone hydrogen bond formed by p73 S261 is also analogous to the interaction of the P− 2 residue of classical SH3 binding motifs (Fig. 8b). The interaction between Cbl-b and CIN85 is itself unusual as the proline–arginine motif of Cbl-b spans across the multiple SH3 domains of CIN85.45

Bottom Line: The loop in p73 is changed by a two-residue insertion that also induces repacking around the site of the p53 mutational hotspot R175.Importantly, the binding of ASPP2 is preserved by conformational changes in both the ankyrin repeat and SH3 domains.These results further highlight the structural variation that impacts p53 family interactions within the p53 interactome.

View Article: PubMed Central - PubMed

Affiliation: Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK.

Show MeSH
Related in: MedlinePlus