Cellular membranes are critical interfaces for the biochemical interactions that regulate cell behavior and function. Composed of heterogeneous mixtures of lipids and proteins, these membranes create complex environments where protein-lipid interactions are functionally coupled, making mechanistic understanding and experimental control particularly challenging. Nonetheless, elucidating these interactions is essential for uncovering disease mechanisms, advancing drug discovery and delivery, and engineering functional biomaterials. Over the past decade, intrinsically disordered proteins (IDPs) have emerged as key regulators of cellular signaling, membrane trafficking, and membrane organization. Lacking stable tertiary structure, IDPs exist as dynamic conformational ensembles with distinct biophysical properties. While interest in IDP-membrane interactions is growing, these interactions remain less well characterized than those of structured proteins. Given that many IDPs localize to or act at membrane surfaces, uncovering how structural disorder governs protein-lipid interactions is critical for understanding membrane-associated processes. To address these challenges, our group applies engineering principles and fluorescence-based techniques to develop new tools and approaches for probing the protein-lipid interface, with a particular emphasis on membrane-binding IDPs.
This presentation will focus on the interplay between membrane physicochemical properties and intrinsically disordered proteins (IDPs), with particular emphasis on how membrane composition and curvature regulate the binding and activity of α-Synuclein (αSyn) – an IDP implicated in Parkinson’s disease. αSyn is a small, 140-residue protein that undergoes a disorder-to-helix transition in its N-terminal 100 residues upon membrane binding, while its remaining 40 C-terminal residues remain extended and loosely associated with the membrane surface. We found that a subtle post-translational modification – N-terminal acetylation – dramatically alters αSyn’s membrane-binding behavior. This finding is particularly significant given that the acetylated form is the physiologically relevant version of the protein, yet much of the literature has focused on the unmodified form. Beyond membrane binding, we also dissect the distinct contributions of αSyn’s N- and C-terminal regions to its ability to drive membrane remodeling. Surprisingly, our results suggest that the extended C-terminal region may play a previously underappreciated role in suppressing membrane deformation and fission. Together, these findings reveal how structural disorder and membrane physicochemical properties together govern the physical behavior of protein-lipid systems. By dissecting the region-specific contributions of αSyn and the impact of post-translational modifications, we provide a mechanistic framework for understanding how disorder tunes membrane binding and remodeling. This work contributes to a broader effort to uncover the physical principles underlying protein function at compositionally complex membrane interfaces.
Wade Zeno joined the Mork Family Department of Chemical Engineering and Materials Science at the University of Southern California in Fall 2020 as an assistant professor. He earned his PhD in Chemical Engineering from the University of California, Davis in 2016 and worked as a postdoctoral fellow in the Biomedical Engineering Department at the University of Texas at Austin until 2020. His research expertise is in biological membrane engineering. Specifically, he examines the molecules that comprise cellular membranes (i.e. proteins and lipids) to understand (i) how they function at a fundamental level and (ii) how they can be exploited to make functional biomaterials. The broader impact of this work spans multiple areas, from uncovering the molecular basis of disease to developing new strategies for therapeutic intervention.