Supported Natural Membranes on Microspheres for Protein−Protein Interaction Studies

Multiple biological and pathological processes, such as signaling, cell−cell communication, and infection by various viruses, occur at the plasma membrane. The eukaryotic plasma membrane is made up of thousands of different lipids, membrane proteins, and glycolipids, and its composition is dynamic and constantly changing. Due to the central importance of membranes on the one hand and their complexity on the other, membrane model systems are instrumental for interrogating membrane-related biological processes. Here, we develop a new tool for protein−membrane interaction studies. Our method is based on natural membranes obtained from extracellular vesicles. We form membrane bilayers supported on polystyrene microspheres that can be trapped and manipulated using optical tweezers. This method allows working with membrane proteins of interest within a background of native membrane components where their correct orientation is preserved. We demonstrate our method’s applicability by successfully measuring the interaction forces between the Spike protein of SARS-CoV-2 and its human receptor, ACE2. We further show that these interactions are blocked by the addition of an antibody against the receptor binding domain of the Spike protein. Our approach is versatile and broadly applicable for various membrane biology and biophysics questions.