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. Author manuscript; available in PMC: 2014 Jul 1.
Published in final edited form as: Cancer Discov. 2013 Nov 21;4(1):80–93. doi: 10.1158/2159-8290.CD-13-0642

Figure 2. Structure-function models of novel mutants in the PI3K-AKT pathway.

Figure 2

A, Schematic protein domains of AKT showing locations of E17K (AKT3) and Q79K (AKT1) substitutions in the PHD (underlined portion represented in 3D). Merged structures of Apo Q79KAKT1 (purple) and IP4-bound Q79KAKT1 (blue) with zoomed-in image (PIP4, orange) showing locations of E17 (green) and relative positions of WT Q79 (yellow) and mutant K79 (red). B, Schematic protein domains of PIK3CA (p110α) and PIK3R2 (p85) showing locations of the PIK3CA D350G (C2 domain) and E545G (helical domain) substitutions. Underlined portions of PIK3CA and homologous PIK3R1 represented as a 3D hetero-dimer (PIK3CA WT, purple; PIK3CA D350G, blue; niSH2 domain of PIK3R1 (p85α), magenta). A zoomed-in view of the interface between the C2 domain of PIK3CA and niSH2 domain of PIK3R2 suggesting the D350G (D350 yellow; G350 red) substitution likely abolishes a critical interaction with the highly conserved S565 (orange) of PIK3R2. C, Schematic protein domains of PIK3CA (p110α) and PIK3R2 (p85) showing location of the PIK3R2 N561D substitution in the iSH helical linker domain. PIK3CA WT (aa 31-515; magenta) in complex with a merged niSH2 domain structure of PIK3R2 WT (purple) and PIK3R2 N561D (blue). A zoomed-in view of the interface between the C2 domain of PIK3CA and niSH2 domain of PIK3R2 showing the interaction between PIK3R2 N561 (yellow) and PIK3CA N345 (orange) being disrupted by the PIK3R2 N561D mutant (red). D, Schematic protein domains of PTEN showing the locations of the frameshift mutation in codon 40 and the deletion of M134. Merged structures of the full-length PTEN WT (purple) with M134 highlighted (yellow) and PTEN M134del (blue) in the dual-specificity phosphatase domain bound by the inhibitor tartrate (orange). A zoomed-in view showing how deletion of the highly conserved M134 (yellow) may destabilize an alpha helical structure proximal to the P loop and alters the critical side chain conformations of the P loop, which is critical for phosphatase activity.