Abstract
The protein family of small GTPases controls cellular processes by acting as a binary switch between an active and an inactive state. The most prominent family members are H-Ras, N-Ras, and K-Ras isoforms, which are highly related and frequently mutated in cancer. Bisphenols are widespread in modern life because of their industrial application as plasticisers. Bisphenol A (BPA) is the best-known member and has gained significant scientific as well as public attention as an endocrine disrupting chemical, a fact that eventually led to its replacement. However, compounds used to replace BPA still contain the molecular scaffold of bisphenols. BPA, BPAF, BPB, BPE, BPF, and an amine-substituted BPAF-derivate all interact with all GDP-bound Ras-Isoforms through binding to a common site on these proteins. NMR-, SOScat-, and GDI- assay-based data revealed a new bisphenol-induced, allosterically activated GDP-bound Ras conformation that define these plasticisers as Ras allosteric agonists.
Highlights
In order for cells to respond to their external microenvironment, proper cell signalling is pivotal
We have shown that Bisphenol A (BPA)—but not Bisphenol S (BPS)—can interfere with the guanine nucleotide exchange factors (GEFs)-mediated nucleotide exchange from guanosine diphosphate (GDP) to guanosine triphosphate (GTP) [10]
We tested the simplest structural bisphenolic ligand, which is BPF carrying two hydrogens instead of two methyl groups in BPA located outside the AFX binding pocket of K-Ras4B, followed by other bisphenol derivatives (Table 1 and Table S1)
Summary
In order for cells to respond to their external microenvironment, proper cell signalling is pivotal. The activation/inactivation GTP/GDP cycle of all Ras-like G-proteins is negatively regulated by GTPase activating proteins (GAPs) and positively influenced by guanine nucleotide exchange factors (GEFs) [3]. These proteins, such as the son of sevenless (Sos) protein and RasGRP1, interact directly with G-proteins and lower the affinity of these (Ras-like) G-proteins for its bound nucleotide [3,4]. The GTPase cycle comprises inactive, GDP-bound and active, GTP-bound states that transmit extracellular within cells by interacting with numerous intracellular effector proteins. This regulatory mechanism enables small GTPases to function as molecular switches in living cells. These key players of the intracellular signalling cascade have been in the focus of numerous cancer drug development initiatives for the more than two decades [5,6,7,8]
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