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Comprehensive Multidimensional NMR Studies on the Interaction Between Ras-Like Gtpases and Bisphenols

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Comprehensive Multidimensional NMR Studies on the Interaction Between Ras-Like Gtpases and Bisphenols Comprehensive multidimensional NMR studies on the interaction between Ras-like GTPases and Bisphenols Dissertation to obtain the degree Doctor Rerum Naturalium (Dr. rer. nat.) at the Faculty of Chemistry and Biochemistry of the Ruhr University Bochum Miriam Schöpel, M. Sc. Biochemistry July 2016 This thesis was completed from May 2013 to July 2016 at the group of biomolecular NMR at the Ruhr University Bochum under the supervision of Prof. Dr. Raphael Stoll. Chair: 1st Examiner: Prof. Dr. Raphael Stoll 2nd Examiner: Prof. Dr. Christian Herrmann Date of Final Examination: Ever tried. Ever failed. No matter. Try Again. Fail again. Fail better. -Samuel Beckett- Content Abstract ...................................................................................................................... 1 Scope of this thesis .................................................................................................... 3 Part I: Introduction ...................................................................................................... 4 1. Introduction ........................................................................................................... 5 1.1. Guanine Nucleotide-binding Proteins (GNBPs) .......................................... 5 1.2. The small GTPase Ras .............................................................................. 9 1.3. The Ras protein in cancers, drugging the undruggable? .......................... 12 1.4. Rap-Proteins ............................................................................................ 15 1.5. Adenylation of small GTPases by Legionella Pneumophila effectors ....... 16 1.6. Bisphenols ................................................................................................ 17 1.7. NMR to characterise protein-ligand interaction ........................................ 21 Part II: Published Papers .......................................................................................... 24 2. Published Paper .................................................................................................. 25 2.1. Paper I: ............................................................................................................ 27 Bisphenol A Binds to Ras Proteins and Competes with Guanine Nucleotide Exchange: Implications for GTPase-Selective Antagonists ......................................................... 27 2.2. Paper II: ........................................................................................................... 57 The Bisphenol A Analogue Bisphenol S binds to K-Ras4B - implications for ‘BPA-free’ plastics ....................................................................................................................... 57 2.3. Paper III ........................................................................................................... 65 Different Bisphenols bind to Ras isoforms and induce a pseudo-active conformation .............................................................................................................. 65 Part III: Summary ...................................................................................................... 83 3. Summary ............................................................................................................. 84 4. Conclusion & Outlook .......................................................................................... 88 Bibliography .............................................................................................................. 89 Curriculum Vitae ....................................................................................................... 97 Acknowledgements ................................................................................................ 100 1 Abstract Ras proteins are key players in a series of cellular signalling pathways, such as proliferation and cell growth. The human Ras family consists of three different members, H-Ras, K-Ras (two isoforms: 4A and 4B), and N-Ras. The Ras gene is tragically famous for being mutated in about 30 % of human cancers. Ras proteins fulfil their cellular role by acting as binary molecular switches: The “on”- or “off” state is characterised by the bound nucleotide (GTP = “on”, GDP = “off”). From a NMR (nuclear magnetic resonance) spectroscopist´s point of view, a protein is a collection of resonances with different frequencies, according to their chemical environment. The popular representation of this point of view is the 2D 1H-15N TROSY- HSQC spectrum, in which every amide proton of an amino acid (besides proline) is represented by a single cross peak. In a simplified manner, the 2D 1H-15N TROSY- HSQC spectrum represents the fingerprint of the protein. Both of Ras´ activation states can be distinguished in these spectra, because of the dynamical and structural properties of each nucleotide binding state. Bisphenols (BPs) are the topic of a heated, as well scientific but also public, discussion. Chemically they share a common attribute in form of two ringed aromatic systems, which are connected by a sp3-hybridised central carbon atom. This bridging moiety can be optionally substituted, leading to a variety of different bisphenols. BPs are used in industrials processes as plasticisers and can be found in different consumer products, like plastic bottles, cashier receipts, and canned foods. This ubiquitous exposure is reflected by the fact, that these compounds are also detectable in human blood, urine, and sweat. In this thesis, the effects of small organic compounds from the class of Bisphenols on the structural and functional properties of Ras and its interaction partners were investigated. The identification of the binding pocket was carried out by the analysis of chemical shift perturbations (CSP-NMR) within a series of 2D 1H-15N TROSY-HSQC spectra. The pocket is located between the α2-helix of Switch II and the central β-sheet of the Ras protein. By plotting the amino acids CSPs versus the ligand concentration, the KD value of every residue can be derived. The extracted KD values are in milli- to micromolar range, an affinity in which also some of Ras´ protein protein interactions are found. 2 Moreover, several chemical shift perturbations for amino acids were observed, which are not part of the binding pocket: G13, D57, G60 (part of the nucleotide binding domain), and Y157. The chemical shift of tyrosine 157 is a valuable tracer for Ras´ toggling between “on”- and “off”-state. The CSPs of these particular showed a ligand- induced shift into the same direction as observed for the active form of the protein, which leads to the conclusion that the different BPs induce a pseudo-activation of the Ras protein. Judged from the NMR spectra, this form has to be different from the original active form, since the specific line broadening of the above mentioned amino acids (G13, D57, and G60) is not observed. In addition to this finding, a fluorescence assay was performed, that probes the SOS-mediated (son of sevenless) nucleotide exchange. The observed rates showed a significant decrease, which can be explained by two models: Firstly, a sterically interference of the ligand upon binding in the Ras- SOS interface and, secondly, a lower affinity of SOS towards Ras, because it is likely that SOS does not bind to the pseudo-activated form of Ras. In a next step, Rap1A and Ras isoforms were tested in order to investigate the selectivity of BPs for small GTPases. The isoforms H-Ras and N-Ras, showed the same binding mode as found for K-Ras4B, except for N-Ras, that exhibits a slightly lower KD. Remarkably, Rap1A showed no binding of bisphenolic compounds. A possible explanation could be that the Switch II region of this proteins is more rigid or at least is characterised by different Switch II dynamics compared to the Ras isoforms, with the result that this protein does not offer a binding pocket for BPs. With this thesis, a direct link between BPs and cancer related Ras isoforms is identified. Based on the observation that BPs modulate the structural and functional properties of these proteins further research is needed to place the results in a larger, more medical, context. 3 Scope of this thesis Protein ligand interactions are essential to almost all processes occurring in living cells, as correct signal transmission is essential for the adaption to the environment. Additionally, they harbour the opportunity to characterise interaction partners on an atomic level and the possibility of therapeutically intervention. In this work, the interaction of various bisphenols, in total 14 (see table 1 in the introduction part), and different Ras proteins has been investigated. The Ras proteins tested, included the three Ras isoforms (H-, N-, K4A, and K4B), and Rap1A (Ras related protein 1). The protein Ras is directly related to various cancer types (like lung, colorectal, and pancreatic cancer), because it controls fundamental processes during cell growth. Rap1A is sequentially highly related to the Ras isoforms but also shows significant differences, including amino acid replacements. The Bisphenols investigated varied in the substitution pattern of the central carbon atom, in order to characterise their structure activity relationship (SAR) properties. Moreover, the NMR-based screening of the different bisphenols was standardised in order to obtain comparable affinity constants (KD-values). The ultimate goal was to evaluate the different bisphenols and proteins based on their interaction,
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