1. What is the new discovery that you made?
In the human cell, the Guanylate Binding Protein 1 (hGBP1), is an active player against bacteria and viruses. Yet, its mechanism of action is poorly understood. We found that the function of hGBP1 is controlled by the molecular energy source Guanosine triphosphate GTP. When bound to other molecules (like the monophosphate GMP or the diphosphate GDP), the hGBP1 remains inactive in the cytosol. If hGBP1 binds to GTP, the structure of the protein changes such that the lipid anchor of hGBP1 (a farnesyl group at the C-terminus of hGBP1) becomes available for additional interactions, which depend on the environment. Away from membranes, the protein forms ring-like and cylindrical polymers with the farnesyl groups as a hydrophobic core. In the vicinity of a membrane, the lipid anchor becomes attached to it and further on leads to tethering of near membrane vesicles.
2. What is its significance?
In fighting pathogens, cells act by engulfing bacteria and viruses inside their membrane, forming a vesicle. The new vesicle then tethers and fuses with lysosomes, cellular organelles which provide the necessary enzymes to degrade the pathogen. The mechanism we hypothesized is a central part of the anti-pathogenic activity of hGBP1: We could show that hGBP1 uses the anchor to tether vesicles and could therefore be directly involved in the step before the fusion that leads to pathogen degradation. Based on our findings, in the future it may be possible to elucidate escape strategies of pathogens as well as to gain deeper understanding of specific pathogen defense.
3. Is this related to Solvation Science? If yes, how?
Yes. The lipid anchor switching response is most sensitive to changes of the solvent environment. For example, small changes of the salt concentration change dramatically polymer formation. But even changes in the protein structure (the basis of the molecular switching) are dependent on the salt concentration. In our future studies we want to find out which parts of the protein are responsible to make the system so sensitive to the solvent environment.