Hierarchical mesoscale domain organization of the plasma membrane

Based on recent single-molecule imaging results in the living cell plasma membrane, we propose a hierarchical architecture of three-tiered mesoscale (2–300 nm) domains to represent the fundamental functional organization of the plasma membrane: (i) membrane compartments of 40–300 nm in diameter due to the partitioning of the entire plasma membrane by the actin-based membrane skeleton ‘fence’ and transmembrane protein ‘pickets’ anchored to the fence; (ii) raft domains (2–20 nm); and (iii) dimers/oligomers and greater complexes of membrane-associated proteins (3–10 nm). The basic molecular interactions required for the signal transduction function of the plasma membrane can be fundamentally understood and conveniently summarized as the cooperative actions of these mesoscale domains, where thermal fluctuations/movements of molecules and weak cooperativity play crucial roles.