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Model membranes and protein-lipid interactions
Membranes are vital for almost all cellular functions. Their structure, function and organization are largely determined by the molecular interactions between membrane constituents, i.e. proteins and lipids within and at membranes. These can be conveniently studied by making use of model membranes. The research is divided over several research lines.
Understanding protein/lipid interactions
The main aim in this research line is to understand how membrane proteins are modulated by lipids in the membrane. Much insight has been obtained by using a bottom-up approach involving simple, artificial model systems of designed transmembrane peptides in synthetic lipid bilayers. The most important advantages of using these systems are that they are relatively easy to study and allow systematic variation of many different parameters (e.g. peptide hydrophobic length, peptide hydrophobicity, bilayer thickness). Thus, these systems are very useful to uncover general principles of protein-lipid interactions in membranes.
WALP peptide that is used as mimic for a transmembrane alpha-helix
For review see e.g. Killian JA and Von Heijne G, How proteins adapt to a membrane-water interface. TIBS 2000 ; 25(9):429-434)
In a complementary line of research, we explore the use of amphipathic polymers of styrene and maleic acid (SMA) as novel tool in membrane research. SMA polymers are able to solubilize membranes in the form of nanodiscs, allowing purification and characterization of membrane proteins directly in their native environment without the use of detergent. We use the SMA technology to solubilize, purify, and characterize membrane proteins in their native lipid environment, and we investigate its mode of action using model membrane systems. In addition we explore new applications of SMA in membrane research, in particular with respect to studying protein/lipid interactions.
Schematic representation of ways of reconstituting membrane proteins in a bilayer environment after purification in micelles (black arrows) versus direct solubilization of membrane proteins from their native environment in the form of native nanodiscs (red arrow).
For review see: Dörr JM, Scheidelaar S, Koorengevel MC, Dominguez JJ, Schäfer M, van Walree CA, Killian JA, The styrene-maleic acid copolymer: a versatile tool in membrane research Eur Biophys J. 2016 ; 45(1):3-21
Amyloid membrane interactions
This research line concerns the interaction of membranes with amyloid forming proteins, which have been associated with a wide range of diseases. Membranes play an important role in the lethal action of these proteins. On one hand they can catalyze fibril formation of amyloid proteins that bind to the membrane surface. On the other hand, fibrils that form on the membrane surface can take up lipids from the membrane and cause membrane defects. In vivo these processes may lead to cell death.
We use synthetic peptides to study the interactions of amyloid forming proteins with (model)membranes and to test effects of inhibitors. For this we mostly use biophysical and biochemical techniques.
The amyloid protein that we focus on is the islet amyloid polypeptide (IAPP) involved in type II diabetes. This is particularly relevant in view of the worldwide increasing prevalence of obesity, which is an important risk factor in development of diabetes.
Models for the hIAPP-membrane interaction in relation to membrane damage and hIAPP cytotoxicity (from reference below).
For review see: Khemtémourian L, Killian JA., Höppener JWM. and Engel MFM, Recent insights in Islet Amyloid Polypeptide-induced membrane disruption and its role in b-cell death in type 2 diabetes mellittus Exp Diabetes Res. 2008 ; 421287.
Role of membranes in tumoricidal and bactericidal effects of non-thermal plasma’s
Plasma medicine involves the generation and application of non-thermal plasmas to deliver a ‘cocktail’ of reactive chemical species, electric charges, electric fields and UV radiation to the target of interest. These plasma’s are able to kill bacterial cells and tumor cells and may do so without harming healthy tissue. Membranes are likely to play an important role in these effects of plasmas. In this new line of research we investigate the effects of plasmas on (model)membranes and in close collaboration with research teams from TU/e, UU and UMCU we aim to find out how membrane effects are related to bactericidal and tumoricidal properties of plasmas. The final aim is to develop and improve applications of non-thermal plasmas to combat (multidrug-resistant) bacterial infections and cancer.
Non-thermal plasmas deliver a chemically rich cocktail of electrical charge, UV radiation, electric field, reactive oxygen species (ROS) and reactive nitrogen species (RNS) to any target. Here as potential targets are shown: lipid vesicles, bacteria, cells in tissue, and a wound. The latter may be the edge of an excised tumor or a wound that is infected with bacteria. (Illustration by dr. Ana Sobota, TU/e)