Examination of Curvature Selectivity as Core Parameter for Temporal and Spatial Protein Organization at Deforming Cellular Membranes

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Signal propagation across cellular membranes relies on dynamic molecular platforms that integrate intra- and extracellular signals to regulate cell shape and function. To correctly respond to an ever-changing environment, activity of these signaling platforms needs to be tightly controlled in space and time. Work in our lab is focused on a particular sub-type of receptor-independent signaling platforms, where physical forces at the plasma membrane are translated into classical biochemical signal transduction cascades via nanoscale membrane deformations. This new type of mechano-chemical signal translation at cellular membranes relies on dynamic recruitment of curvature-sensing signaling molecules to transiently deformed membranes. In the proposed project, we aim to investigate the molecular mechanisms responsible for the creation of functionally distinct curvature-dependent signaling hubs. Specifically, we aim to answer: (I) Whether differences in membrane curvature selectivity of individual proteins are sufficient to control the temporal order in which curvature-sensing signaling proteins appear at a spontaneously deforming plasma membrane. (II) If differences in membrane curvature selectivity of individual proteins can lead to asymmetric spatial organization of these proteins in aggregates that form at curved membranes. To address these questions, we will combine novel types of nanomaterials with advanced image analysis methods in live cells and artificial membranes. Functional consequences of differences in spatial and temporal recruitment dynamics on mechano-chemical signal conversion will be investigated using curvature-dependent regulation of actin polymerization dynamics in lamellipodia and filopodia as model systems. The proposed project is relevant as it will provide evidence that curvature-selectivity is sufficient to organize localization of curvature-sensing proteins in space and time, and in consequence to control protein composition at signaling hubs. Insights from these studies will advance our understanding of how membrane curvature contributes to a variety of cellular processes, (e.g. cell motility, bacterial pathogenesis, as well as vesicle endocytosis and fusion), and provide new inroads to better understand disease involving defective curvature-sensing signaling proteins (e.g. srGAP3 in mental retardation, Oligophrenin in fragile X syndrome).