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Messing Up Disorder: How Do Missense Mutations in the Tumor Suppressor Protein APC Lead to Cancer?


Messing Up Disorder: How Do Missense Mutations in the Tumor Suppressor Protein APC Lead to Cancer?

David P Minde et al. Mol Cancer.


Mutations in the adenomatous polyposis coli (APC) tumor suppressor gene strongly predispose to development of gastro-intestinal tumors. Central to the tumorigenic events in APC mutant cells is the uncontrolled stabilization and transcriptional activation of the protein β-catenin. Many questions remain as to how APC controls β-catenin degradation. Remarkably, the large C-terminal region of APC, which spans over 2000 amino acids and includes critical regions in downregulating β-catenin, is predicted to be natively unfolded. Here we discuss how this uncommonly large disordered region may help to coordinate the multiple cellular functions of APC. Recently, a significant number of germline and somatic missense mutations in the central region of APC were linked to tumorigenesis in the colon as well as extra-intestinal tissues. We classify and localize all currently known missense mutations in the APC structure. The molecular basis by which these mutations interfere with the function of APC remains unresolved. We propose several mechanisms by which cancer-related missense mutations in the large disordered domain of APC may interfere with tumor suppressor activity. Insight in the underlying molecular events will be invaluable in the development of novel strategies to counter dysregulated Wnt signaling by APC mutations in cancer.


Figure 1
Figure 1
The human APC protein carries a large predicted disordered domain which is frequently hit by missense mutations in cancer. (A) Schematic representation of the APC scaffold protein and its protein interaction domains. Known interactors are APC (green), CRM1 (orange), PP2A (brown), β-catenin, CtBP (15aa repeats, blue), β-catenin (20 aa repeats, cyan), sequence B (yellow), Axin (SAMP-repeats, purple), Microtubules (dark green) and EB1 (light green). (B) Summary of disorder predictions performed for full-length human APC using different algorithms from publicly available servers [31-35]. Sequence segments with disorder probability above 50% are represented as black bars. (C) Distribution of missense mutations in the APC protein reported in various tumors, categorized as somatic (red), germline (black) or unknown origin (grey). Details on the location and nature of amino acid substitutions can be found in additional file 1, Table S1. (D) Summary of disorder predictions performed for β-catenin (black bars), done as in (B), and β-catenins's helical secondary structure elements as determined by crystallography (gray bars) [36].
Figure 2
Figure 2
Structural organization of the largely unfolded human APC protein. Scaled representation of APC as a large and highly flexible protein with only a few folded segments located at its N-terminus. Folded domains, extended regions and their binding partners are indicated with a color code as in Figure 1. The extended conformation of the predicted disordered domain (F800 - V2843) is reflected by the increased protein length per amino acid residue. The relative scale indicates the maximally possible length of fully extended APC. For comparison of protein compactness, a schematic representation of the tightly folded Armadillo repeat domains of β-catenin (spanning 510 residues, comprising 10 nm only, dark blue rectangle) is depicted to scale.
Figure 3
Figure 3
Missense mutations cluster outside the β-catenin binding motifs in the MCR of APC. (A) Closeup on missense mutation frequency in MCR. Color code as in Figure 1C. (B) Domain structure of the MCR, color code as in Figure 1A. We calculated mutation frequency by dividing the number of mutations in a particular codon by the total number of missense mutations reported in all referenced studies.

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