Abstract
Mammalian cell function requires timely and accurate transmission of information from the cell membrane (CM) to the nucleus (N). These pathways have been intensively investigated and many critical components and interactions have been identified. However, the physical forces that control movement of these proteins have received scant attention. Thus, transduction pathways are typically presented schematically with little regard to spatial constraints that might affect the underlying dynamics necessary for protein-protein interactions and molecular movement from the CM to the N. We propose messenger protein localization and movements are highly regulated and governed by Coulomb interactions between: 1. A recently discovered, radially directed E-field from the NM into the CM and 2. Net protein charge determined by its isoelectric point, phosphorylation state, and the cytosolic pH. These interactions, which are widely applied in elecrophoresis, provide a previously unknown mechanism for localization of messenger proteins within the cytoplasm as well as rapid shuttling between the CM and N. Here we show these dynamics optimize the speed, accuracy and efficiency of transduction pathways even allowing measurement of the location and timing of ligand binding at the CM –previously unknown components of intracellular information flow that are, nevertheless, likely necessary for detecting spatial gradients and temporal fluctuations in ligand concentrations within the environment. The model has been applied to the RAF-MEK-ERK pathway and scaffolding protein KSR1 using computer simulations and in-vitro experiments. The computer simulations predicted distinct distributions of phosphorylated and unphosphorylated components of this transduction pathway which were experimentally confirmed in normal breast epithelial cells (HMEC).
Highlights
Normal mammalian cell function requires continuous processing of environmental information encoded in ligands that bind to cell membrane (CM) receptors [1]
Our fundamental hypothesis [1,10] is protein movement and localization is, highly regulated through Coulombic interaction between the net electric charge of messenger proteins and a recently-measured intracytoplasmic electric (E) field governs protein movement and localization within the cytosol. We propose these dynamical interactions represent a critical but previously unknown component of cellular biology that optimizes signal transduction and information acquisition
We focus on movement and interactions of the 3 proteins that carry the signal from the CM to the N following ligand binding to epidermal growth factor receptor (EGFR): RAF, MEK, and ERK (Figure 1) [3,4,15]
Summary
Normal mammalian cell function requires continuous processing of environmental information encoded in ligands that bind to cell membrane (CM) receptors [1]. Proteins may be transported via cytoplasmic streaming and microtubular networks, multiple studies have demonstrated messenger proteins move freely in the cytoplasm [5,6,7,8,9]. In the current cell model, protein communication networks are usually depicted schematically with little consideration of the actual physical motion of the constituent proteins. In the MAPK pathway (see Figure 1), for example, the movement of the messenger proteins is not explicitly integrated into the model but it appears that random motion is sufficient to permit the protein-protein interactions and movement to the N. Signal flow from the CM to NM requires a diffusion distance of about 1,000 protein diameters
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