Membrane-decisional architecture: a framework for multigenomic signal prioritization in the plasma membrane nanobiome.

BACKGROUND: Classical models of cellular signaling assume that ligand recognition at the plasma membrane is sufficient to initiate intracellular cascades. However, experimental evidence consistently shows that extracellular signals can engage receptors without producing functional cellular responses and that identical ligand-receptor interactions may generate divergent outcomes depending on membrane organization, receptor clustering, and intracellular routing dynamics. CONCEPTUAL FRAMEWORK: To address this discrepancy, the concept of membrane-decisional architecture is introduced, in which plasma membrane organization is interpreted as a signal prioritization interface. Within this framework, membrane structure governs signaling competence by regulating signal access, receptor clustering, intracellular routing, and compartmental signal conversion, thereby determining which extracellular inputs acquire functional relevance. METHODS: A structured integrative synthesis was conducted using a Work Breakdown Structure (WBS) framework (WP1-WP5), encompassing evidence acquisition, mechanistic mapping, integrative synthesis, cross-system structural calibration, and formal systems integration. Mechanistic findings from membrane biology and cellular signaling were reorganized to evaluate whether a coherent architecture of signaling competence emerges across biological systems. A conceptual mathematical formalization was developed to represent the relationship between signal availability and membrane-dependent competence. IMPLICATIONS: This framework does not propose new molecular mechanisms but provides an integrative interpretation of how established membrane-level processes collectively constrain signaling outcomes under heterogeneous input conditions. Membrane organization is therefore positioned as an upstream determinant of cellular responsiveness. The proposed formalization provides a basis for experimental investigation of membrane-dependent signaling competence and its role in physiological variability.