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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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Related in: MedlinePlus

The p73 structure contains a divergent L2 loop. (a) Superposition of the free p53 (orange) and p73 (green) structures highlighting the different L2 loop conformations. (b) In both structures, conserved residues in the L2 loop form hydrogen bonds to a buried, ordered water molecule. (c) Salt bridge and hydrogen bond interactions in the p53 L2 loop. The R175 and D184 positions are highlighted. (d) The p73 L2 loop harbors a two-residue insertion (sequence alignments indicate insertion of p73 F203 and Q207 shown labeled in italics). As a result, the L2 loop structure and hydrogen bonding are changed. Most notably, the p53 R175–D184 salt bridge (equivalent to p73 residues R193 and D202 labeled in boldface) is replaced by p73 R193 interaction with N204. The N204 side chain also forms two hydrogen bonds to the H1 helix that are absent in p53.
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f0025: The p73 structure contains a divergent L2 loop. (a) Superposition of the free p53 (orange) and p73 (green) structures highlighting the different L2 loop conformations. (b) In both structures, conserved residues in the L2 loop form hydrogen bonds to a buried, ordered water molecule. (c) Salt bridge and hydrogen bond interactions in the p53 L2 loop. The R175 and D184 positions are highlighted. (d) The p73 L2 loop harbors a two-residue insertion (sequence alignments indicate insertion of p73 F203 and Q207 shown labeled in italics). As a result, the L2 loop structure and hydrogen bonding are changed. Most notably, the p53 R175–D184 salt bridge (equivalent to p73 residues R193 and D202 labeled in boldface) is replaced by p73 R193 interaction with N204. The N204 side chain also forms two hydrogen bonds to the H1 helix that are absent in p53.

Mentions: As a consequence of their relatively high cysteine content, p53 family members have been identified as redox‐sensitive proteins.29 Of the 10 cysteine residues found in the p53 DBD, 7 are conserved in p73 (Supplementary Fig. S1). Unusually, a disulfide bond is observed in the p73 structure between C153 (S2′) and C159 (S3), although the main‐chain atoms remain similarly placed to p53 C135 and C141 (Supplementary Fig. S1c), suggesting that the oxidation has limited structural significance and is most likely the result of insufficiently reducing conditions during purification. The same site in p53 has a third cysteine residue C124 (β-strand S2) in close proximity, which may increase the propensity for p53 misfolding upon oxidation. The two remaining cysteine substitutions include p73 F249 and G200, which replace p53 C229 and C182, respectively. The smaller substitution of G200 stabilizes the p73 H1 helix in a distinct conformation of the L2 loop that facilitates hydrogen bond formation between G200 and N204 (Fig. 4a and d).


Structural basis for ASPP2 recognition by the tumor suppressor p73.

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

The p73 structure contains a divergent L2 loop. (a) Superposition of the free p53 (orange) and p73 (green) structures highlighting the different L2 loop conformations. (b) In both structures, conserved residues in the L2 loop form hydrogen bonds to a buried, ordered water molecule. (c) Salt bridge and hydrogen bond interactions in the p53 L2 loop. The R175 and D184 positions are highlighted. (d) The p73 L2 loop harbors a two-residue insertion (sequence alignments indicate insertion of p73 F203 and Q207 shown labeled in italics). As a result, the L2 loop structure and hydrogen bonding are changed. Most notably, the p53 R175–D184 salt bridge (equivalent to p73 residues R193 and D202 labeled in boldface) is replaced by p73 R193 interaction with N204. The N204 side chain also forms two hydrogen bonds to the H1 helix that are absent in p53.
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f0025: The p73 structure contains a divergent L2 loop. (a) Superposition of the free p53 (orange) and p73 (green) structures highlighting the different L2 loop conformations. (b) In both structures, conserved residues in the L2 loop form hydrogen bonds to a buried, ordered water molecule. (c) Salt bridge and hydrogen bond interactions in the p53 L2 loop. The R175 and D184 positions are highlighted. (d) The p73 L2 loop harbors a two-residue insertion (sequence alignments indicate insertion of p73 F203 and Q207 shown labeled in italics). As a result, the L2 loop structure and hydrogen bonding are changed. Most notably, the p53 R175–D184 salt bridge (equivalent to p73 residues R193 and D202 labeled in boldface) is replaced by p73 R193 interaction with N204. The N204 side chain also forms two hydrogen bonds to the H1 helix that are absent in p53.
Mentions: As a consequence of their relatively high cysteine content, p53 family members have been identified as redox‐sensitive proteins.29 Of the 10 cysteine residues found in the p53 DBD, 7 are conserved in p73 (Supplementary Fig. S1). Unusually, a disulfide bond is observed in the p73 structure between C153 (S2′) and C159 (S3), although the main‐chain atoms remain similarly placed to p53 C135 and C141 (Supplementary Fig. S1c), suggesting that the oxidation has limited structural significance and is most likely the result of insufficiently reducing conditions during purification. The same site in p53 has a third cysteine residue C124 (β-strand S2) in close proximity, which may increase the propensity for p53 misfolding upon oxidation. The two remaining cysteine substitutions include p73 F249 and G200, which replace p53 C229 and C182, respectively. The smaller substitution of G200 stabilizes the p73 H1 helix in a distinct conformation of the L2 loop that facilitates hydrogen bond formation between G200 and N204 (Fig. 4a and d).

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