The plasma membrane is the outermost cellular membrane, which encloses the entire cell. It defines the space for the fundamental unit of life, the cell. The plasma membrane exchanges information, energy, and substances with the outside world, but more interestingly, it functions as a computer to regulate these exchanges. All plasma membranes on earth have the common structure of a "two-dimensional liquid." This raises the possibility that we can identify the set of physical properties of the plasma membrane, like those of DNA, that make the plasma membrane work. Such fundamental mechanisms are likely to be those utilizing the two-dimensionality and modifying the fluidity of the plasma membrane, which we call "membrane mechanisms." The "Membrane Mechanisms Project" seeks to elucidate such fundamental strategies for the functions of the plasma membrane, with special attention paid to its role in signal transduction.
This international joint research project was conducted by combining single-molecule tracking in living cells by the Japanese team, and nano-second fluorescence resonance energy transfer imaging by the Indian team. Four membrane mechanisms have been identified. (1) Low dimensionality, which greatly enhances molecular assembly. In particular, the presence of transient dimers and oligomers of several nanometers in size. (2) Metastability, involving molecules with various degrees of (im)miscibility, leading to the cooperative assembly and disassembly of microdomains ranging from several to tens of nanometers, including raft domains. (3) Partitioning of the entire plasma membrane into 30 to 200 nm compartments by the actin-based membrane skeleton (fence) and transmembrane proteins anchored to the membrane-skeleton fence (pickets), where the hydrodynamic friction effect plays a key role. (4) 2D surface reaction field in 3D space, where molecules can diffuse even after being adsorbed. The hierarchical organization of the first three mesostructures (3 to 300 nm) forms the fundamental structure of the plasma membrane.
In the plasma membrane, these four mechanisms work in concert. For example, in signal transduction, engaged receptors often form oligomers, which are enhanced by transient oligomers before stimulation. When raft-associated receptors are engaged and form oligomers, these oligomers induce stable raft domains, where cytoplasmic signaling molecules are recruited with the aid of the actin-based membrane skeleton and interact efficiently with each other, due to the small, confined space of the raft domain. These results address the fundamental question of how the cell, the basic unit of life, works, and provide important suggestions for developing methods for better diagnoses and treatments in medicine.