Molecular basis of S100 proteins interacting with the p53 homologs p63 and p73

Abstract

S100 proteins modulate p53 activity by interacting with its tetramerization (p53TET, residues 325-355) and transactivation (residues 1-57) domains. In this study, we characterized biophysically the binding of S100A1, S100A2, S100A4, S100A6 and S100B to homologous domains of p63 and p73 in vitro by fluorescence anisotropy, analytical ultracentrifugation and analytical gel filtration. We found that S100A1, S100A2, S100A4, S100A6 and S100B proteins bound different p63 and p73 tetramerization domain variants and naturally occurring isoforms with varying affinities in a calcium-dependent manner. Additional interactions were observed with peptides derived from the p63 and p73 N-terminal transactivation domains. Importantly, S100 proteins bound p63 and p73 with different affinities in their different oligomeric states, similarly to the differential modes of binding to p53. On the basis of our data, we hypothesize that S100 proteins regulate the oligomerization state of all three p53 family members and their isoforms, with a potential physiological relevance in developmental and disease-related processes. The regulation of the p53 family by S100 is complicated and depends on the target preference of each individual S100 protein, the concentration of the proteins and calcium, as well as the splicing variation of p63 or p73. Our results outlining the complexity of the interaction should be considered when studying the functional effects of S100 proteins in their biological context.

The E-F Hand Calcium-Binding Protein S100A4 Regulates the Proliferation, Survival and Differentiation Potential of Human Osteosarcoma Cells

“…S100A4 binds to calcium as a dimer, which induces a conformational change and enables binding to its target proteins [55]. S100 proteins have been shown to modulate cell proliferation by targeting proteins critical to cell cycle regulation [54,56,57]. Our results indicate that S100A4 overexpression not only induces cell proliferation, but also has an inhibitory effect on apoptotic cascade.…”

“…S100A4 binds p53 in a calcium dependent manner through dimerization and promotes p53 degradation [57][58][59]. Furthermore, S100A4 can interfere with the phosphorylation of p53, preventing cells from undergoing apoptosis [23,57,58]. Conversely, the decreased survival observed in OS cells with S100A4 knockdown may be due to the effect of S100A4 on apoptosis.…”

“…A possible explanation may lie in the ability of S100A4 to bind p53, a regulator of the cell cycle, DNA repair, and apoptosis. S100A4 binds p53 in a calcium dependent manner through dimerization and promotes p53 degradation [57][58][59]. Furthermore, S100A4 can interfere with the phosphorylation of p53, preventing cells from undergoing apoptosis [23,57,58].…”

Effects of Levetiracetam on neural tube development and closure of the chick embryos in ovo

“…Adverse outcomes of antiepileptic drug exposure is related to neuronal apoptosis during late gestation and the perinatal period. Calciumdependent interaction of S100 proteins with p63 and p73 has been physiologically relevant in both developmental and disease-related processes [33]. S100 proteins probably plays a role in stimulating neuronal differentiation, proliferation of astrocytes.…”

The Calcium-binding Protein S100B Down-regulates p53 and Apoptosis in Malignant Melanoma

“…However, studies from the Fersht group have begun to identify the source of these discrepancies, because they have discovered that several S100 proteins can interact with p53 and that these S100 proteins interact with the transactivation and/or the C terminus of p53 with affinities that vary by as much as an order of magnitude for two specific sites on p53 (31)(32)(33)76). With this information in mind, it now becomes important to know the relative amount of each member of the S100 protein family member within a particular cell type, because their abundance could result in different functional outcomes with regard to p53 activity.…”