Structural basis for ASPP2 recognition by the tumor suppressor p73.
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.
Affiliation: Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK.Show MeSH
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Mentions: The p73 structure shows a conserved domain architecture, comprising a β-sandwich scaffold consisting of two antiparallel β-sheets (Fig. 1).27 The DNA-binding surface is constructed similarly from the large L2 and L3 loops, the S10 β-strand and a loop–sheet–helix motif that includes the L1 loop, the S2 and S2′ β-strands and the C-terminal H2 α-helix. A conserved zinc ion coordinates the L2 and L3 loops (p73 C194, H197, C258 and C262; Supplementary Fig. S1a) and contributes to the stability of the overall fold. The p73 structure also includes a second metal ion (Supplementary Fig. S1b) trapped at the interface of a crystallographic dimer formed by the H2 helix and the C-terminal His-tag (Supplementary Fig. S2). Here, the coordinating residues include the side chains of C295, C297 and D301 from one monomer and H308 from the second monomer (Supplementary Fig. S2). Both metal ions were confirmed as zinc based on multiwavelength anomalous diffraction data (Supplementary Fig. S3).
Affiliation: Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK.