Intrinsically disordered proteins (IDPs) play important roles in cellular signaling and regulation and are associated with numerious human diseases including cancers. The disordered ensemble of an IDP itself could serve as the central conduit of cellular signaling. The functional mechanism may be encoded in how the disordered ensemble as a whole responds to various stimuli, may it be cooperative binding-induced folding or redistribution of conformational sub-states in dynamic interactions. Using tumor suppressor p53 as an important model system, we combine NMR, binding assay and atomistic simulations to show that cancer-associated mutations as well as anti-tumor drug molecules can modulate the disordered ensemble of p53 to affect its homeostatsis and tumor suppressor function. Our work also highlights the importance and challenges of qunatitative characterization of the disordered ensemble in studies of IDPs.

Central roles of the disordered ensemble in p53 homeostasis and inhibition

ACS Spring 2022

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