R337H mutation is highly associated with childhood adrenocortical carcinoma (ACT) in southern Brazil. The mutant tetramerization domain (p53tet-R337H) adopts a native-like fold but is less stable than the wild-type domain (p53tet-wt). The stability of p53tet-R337H is highly sensitive to pH in the physiological range and correlates with the protonation state of the mutated His 337. (DiGiammarino EL, Lee AS, Cadwell C, Zhang W, Bothner B, Ribeiro RC, Zambetti G, Kriwacki RW. (2002). A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer. Nat Struct Biol. 9:12-16)
Both mutant p53tet-R337H and (pH4.0 and 5.0) and p53tet-wt (pH4.0) form amyloid-like ribbons when incubated at room temperature (22 C) for one month. However, p53tet-R337H, and not p53tet-wt, readily form ribbons at pH4.0 and 37 over 20 hours, suggesting that the mutant p53tet-R337H has a significantly higher propensity to form amyloid-like fibrils.The formation of amyloid is reversible when pH is raised from pH4.0 to pH8.5. (Lee AS, Galea C, DiGiammarino EL, Jun B, Murti G, Ribeiro RC, Zambetti G, Schultz CP, Kriwacki RW. (2003). Reversible amyloid formation by the p53 tetramerization domain and a cancer-associated mutant. J Mol Biol. 327:699-709)
Recent study shows that the disruption of an intermonomer salt bridge Arg337-Asp352 in the p53 tetrameriztion domain results in the increased propensity to form amyloid fibrils. (Galea C, Bowman P, Kriwacki RW. (2005). Disruption of an intermonomer salt bridge in the p53 tetramerization domain results in an increased propensity to form amyloid fibrils. Protein Sci. 14:2993-3003)
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