Structure–function–rescue: the diverse nature of common p53 cancer mutants

Abstract

The tumor suppressor protein p53 is inactivated by mutation in about half of all human cancers. Most mutations are located in the DNA-binding domain of the protein. It is, therefore, important to understand the structure of p53 and how it responds to mutation, so as to predict the phenotypic response and cancer prognosis. In this review, we present recent structural and systematic functional data that elucidate the molecular basis of how p53 is inactivated by different types of cancer mutation. Intriguingly, common cancer mutants exhibit a variety of distinct local structural changes, while the overall structural scaffold is largely preserved. The diverse structural and energetic response to mutation determines: (i) the folding state of a particular mutant under physiological conditions; (ii) its affinity for the various p53 target DNA sequences; and (iii) its protein-protein interactions both within the p53 tetramer and with a multitude of regulatory proteins. Further, the structural details of individual mutants provide the basis for the design of specific and generic drugs for cancer therapy purposes. In combination with studies on second-site suppressor mutations, it appears that some mutants are ideal rescue candidates, whereas for others simple pharmacological rescue by small molecule drugs may not be successful.

Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells

“…It has been shown that the zinc atom is important in stabilizing the DNA-binding domain structure of p53 (Cho et al, 1994) and for p53 DNA-binding activity in vitro and in vivo (Verhaegh et al, 1998). As a proof of principle, some p53 mutations in cancers (for example, mutation C242S, H179R, C176F and R175H) that perturb the zincbinding site in p53 result in the loss of DNA binding (Joenger and Fersht, 2007). Studies in vitro show that In the absence of HIPK2 (that binds p300 and stimulates p53/p300 corecruitment onto apoptotic target genes), Lys382 acetylation is inhibited and Ser46 phosphorylation alone is not sufficient to induce p53 apoptotic transcription.…”

Updates on p53: modulation of p53 degradation as a therapeutic approach

“…A majority of the mutations in p53 are located in the DNA-binding domain, with complex functional consequences. These mutations can affect the thermodynamic stability, folding rates of p53 and the interactions of p53 with DNA as well as with other partner proteins (Joerger and Fersht, 2007). Discovery of second site mutations that restore the activity of some of these mutants has provided clues for the restoration of activity by the use of small molecules.…”

Interactions of mutant p53 with DNA: guilt by association

“…The disclosure of the structure of a co-crystal formed by the p53-DBD and a canonical p53 half-site revealed the principal features of the p53-DBD/DNA interface and formed the basis for understanding the structural premises underlying the loss of the sequence-specific transactivation function by mutp53 proteins (Cho et al, 1994). Since these seminal findings, the understanding of the biology of mutp53 proteins has advanced enormously, the quintessence being the realization that mutp53 proteins are extremely heterogeneous in their structural and possibly also in their biochemical properties (see Joerger and Fersht, 2007, this issue; reviewed by Sigal and Rotter, 2000). Underscoring the inequality of structural defects in the core domains of mutp53 proteins, the major activity of the core domain, SSDB, is impaired in individual mutp53 proteins to different degrees, with the severity of SSDB impairment spanning a broad range (see Joerger and Fersht, 2007;Menendez et al, 2007, this issue;Inga et al, 2001;Ang et al, 2006).…”

“…Since these seminal findings, the understanding of the biology of mutp53 proteins has advanced enormously, the quintessence being the realization that mutp53 proteins are extremely heterogeneous in their structural and possibly also in their biochemical properties (see Joerger and Fersht, 2007, this issue; reviewed by Sigal and Rotter, 2000). Underscoring the inequality of structural defects in the core domains of mutp53 proteins, the major activity of the core domain, SSDB, is impaired in individual mutp53 proteins to different degrees, with the severity of SSDB impairment spanning a broad range (see Joerger and Fersht, 2007;Menendez et al, 2007, this issue;Inga et al, 2001;Ang et al, 2006). However, except for the residual SSDB activity retained by the core domain of some mutp53 proteins, the principles of DNA recognition by mutp53 proteins and the role of mutp53 DNA binding for the oncogenic activities associated with some mutp53 proteins remains far from being clear.…”