Probing the Conformational Diversity of Cancer-Associated Mutations in p53 with Ion-Mobility Mass Spectrometry

摘要

The tumor suppressor p53 is the most mutated protein in human cancers. It is implicated in lung (70%), colon (60%), and stomach (45 %) cancers, respectively. The latest release (R16) of the International Agency for Research on Cancer (IARC) TP53 mutation database contains 29575 somatic mutations (November 2012; http://www-p53.iarc.fr/). A distinctive feature of the p53 mutational map is the rate of occurrence of missense mutations. Indeed, these single-point amino acid substitutions in p53 lead to abrogation of protein function, rather than deletions or nonsense mutations, as it is the case with most tumour suppressor proteins. A technique that is able to rapidly distinguish p53 mutants at low concentrations could have marked benefits for cancer screening assays and also for drug discovery. In this study, we used ion-mobility mass spectrometry (IM-MS) for this task.