Biophysical Society Conference | Tahoe 2024

Molecular Biophysics of Membranes

Thursday Speaker Abstracts

FUNCTIONAL DISORDER AT BIOLOGICAL MEMBRANES Wade F. Zeno ; 1 University of Southern California, Chemical Engineering, Los Angeles, CA, USA The prevailing structure-function paradigm posits that protein function only arises from specific structural features. However, our recent work has revealed that proteins lacking secondary structure – Intrinsically Disordered Proteins (IDPs) – can be potent sensors and generators of membrane curvature. The mechanisms for this functional behavior arise from the polyampholytic nature of these unfolded, amino acid chains. This characteristic imbues IDPs with unique biophysical properties when they come into proximity of biological membranes. Interestingly, IDPs comprise ~40% of the human proteome but only a handful of IDPs have been examined in the context of protein-lipid interactions. Therefore, this paradoxical finding represents a significant, yet unexplored frontier in the field of membrane remodeling. Our most recent findings highlight an example of this disordered functionality in α -Synuclein, which is a neuronal protein that interacts with synaptic vesicles and is heavily implicated with the onset of Parkinson’s Disease. We explore the complex interplay between membrane composition and protein sequence in protein-lipid interactions. Specifically, we find that the C-terminal domain of α -Synuclein contributes to electrostatic repulsion with bilayer surfaces, ultimately regulating its ability to sense and generate membrane curvature. These interactions are highly sensitive to membrane composition. We also investigate the dynamics of these protein-lipid interactions as a function of membrane physiochemical properties. Our work provides fundamental mechanistic insight into the biophysical function of IDPs, which are an underappreciated class of proteins in membrane remodeling processes.

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