Recognition of the tumor suppressor protein p53 and other protein targets by the calcium-binding protein S100B

Abstract

S100B is an EF-hand containing calcium-binding protein of the S100 protein family that exerts its biological effect by binding and affecting various target proteins. A consensus sequence for S100B target proteins was published as (K/R)(L/I)xWxxIL and matches a region in the actin capping protein CapZ (V.V. Ivanenkov, G.A. Jamieson, Jr., E. Gruenstein, R.V. Dimlich, Characterization of S-100b binding epitopes. Identification of a novel target, the actin capping protein, CapZ, J. Biol. Chem. 270 (1995) 14651-14658). Several additional S100B targets are known including p53, a nuclear Dbf2 related (NDR) kinase, the RAGE receptor, neuromodulin, protein kinase C, and others. Examining the binding sites of such targets and new protein sequence searches provided additional potential target proteins for S100B including Hdm2 and Hdm4, which were both found to bind S100B in a calcium-dependent manner. The interaction between S100B and the Hdm2 and/or the Hdm4 proteins may be important physiologically in light of evidence that like Hdm2, S100B also contributes to lowering protein levels of the tumor suppressor protein, p53. For the S100B-p53 interaction, it was found that phosphorylation of specific serine and/or threonine residues reduces the affinity of the S100B-p53 interaction by as much as an order of magnitude, and is important for protecting p53 from S100B-dependent down-regulation, a scenario that is similar to what is found for the Hdm2-p53 complex.

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

“…In summary, the data presented here are consistent with a mechanism in which elevated S100B levels found in malignant melanoma contribute to the down-regulation of the p53 tumor suppressor via a direct S100B-p53 protein-protein interaction observed previously (28). Such an interaction may occur by S100B destabilizing p53 and/or preventing the formation of p53 oligomers, as observed previously (23,(31)(32)(33) and by NMR from our group (data not shown).…”

“…Additionally, it is possible that elevated S100B blocks covalent modification of p53 (i.e. phosphorylation and acetylation) in cells as was observed previously in vitro, which could also contribute to p53 down-regulation (28). Thus, in either case, melanoma cells overexpressing S100B are unable to efficiently undergo apoptosis even when treated with UV radiation, because they have lower than normal levels of p53 and/or phosphorylated p53 protein.…”

“…As pointed out by Fersht and colleagues (31)(32)(33), several S100 proteins bind both the transactivation domain of p53 as well as the C terminus of p53 with varying affinities, and these S100-p53 protein-protein interactions are regulated by posttranslational modifications (i.e. phosphorylation and acetylation) (28,33). Such data provide additional explanations for why the effects of S100 proteins on p53 may be different in various cell types particularly, because S100 proteins themselves are cell specifically distributed (13).…”

“…1-3, supplemental Figs. 2S and 3S), and previously (26,27), was likely the result of a direct S100B-p53 protein-protein interaction detected in vitro (23,24,26,28,(31)(32)(33) and via coimmunoprecipitation from C8146A cells (26).…”

Calmodulin and S100A1 Protein Interact with N Terminus of TRPM3 Channel

“…The parameter r max is the anisotropy at saturation, r obs is the observed anisotropy for any TRPM3 protein concentration, and r min is the minimum observed anisotropy for the free CaM or S100A1. F B was plotted against TRPM3 protein concentration and fitted using Equation 2 (18) to determine the equilibrium dissociation constant (K D ) for TRPM3 /CaM, TRPM3 291-382 /CaM, TRPM3 35-124 /S100A1, and TRPM3 291-382 /S100A1 complex formation.…”