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Review
. 2003 Jul 8;100(14):8053-8.
doi: 10.1073/pnas.1332550100. Epub 2003 Jun 27.

Dynamic, yet structured: The cell membrane three decades after the Singer-Nicolson model

G Vereb  1 , J Szöllosi, J Matkó, P Nagy, T Farkas, L Vigh, L Mátyus, T A Waldmann, S Damjanovich
Affiliations
Review

Dynamic, yet structured: The cell membrane three decades after the Singer-Nicolson model

G Vereb et al. Proc Natl Acad Sci U S A. .

Abstract

The fluid mosaic membrane model proved to be a very useful hypothesis in explaining many, but certainly not all, phenomena taking place in biological membranes. New experimental data show that the compartmentalization of membrane components can be as important for effective signal transduction as is the fluidity of the membrane. In this work, we pay tribute to the Singer-Nicolson model, which is near its 30th anniversary, honoring its basic features, "mosaicism" and "diffusion," which predict the interspersion of proteins and lipids and their ability to undergo dynamic rearrangement via Brownian motion. At the same time, modifications based on quantitative data are proposed, highlighting the often genetically predestined, yet flexible, multilevel structure implementing a vast complexity of cellular functions. This new "dynamically structured mosaic model" bears the following characteristics: emphasis is shifted from fluidity to mosaicism, which, in our interpretation, means nonrandom codistribution patterns of specific kinds of membrane proteins forming small-scale clusters at the molecular level and large-scale clusters (groups of clusters, islands) at the submicrometer level. The cohesive forces, which maintain these assemblies as principal elements of the membranes, originate from within a microdomain structure, where lipid-lipid, protein-protein, and protein-lipid interactions, as well as sub- and supramembrane (cytoskeletal, extracellular matrix, other cell) effectors, many of them genetically predestined, play equally important roles. The concept of fluidity in the original model now is interpreted as permissiveness of the architecture to continuous, dynamic restructuring of the molecular- and higher-level clusters according to the needs of the cell and as evoked by the environment.

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Figures

Fig. 1.
Fig. 1.
Proteins experience different types of restrictions to translational diffusion in the plasma membrane. The view of the membrane is shown from beneath. A, Proteins showing preferential accumulation in a lipid microdomain may be confined to the area of the microdomain if the activation energy of passing the domain barrier is larger than the kinetic energy of the protein. The extent to which passing a domain barrier is prohibited is determined by the preference of the protein for the lipid environment: if the protein interacts preferentially and avidly with lipids of the microdomain, it may be reluctant to leave. B and C, The cytoskeleton is also important in restricting free, lateral diffusion of membrane proteins. Proteins whose intracellular domain is long are unable to pass through a fence composed of a filament of the cytoskeleton (B), whereas proteins with a short intracellular domain are free to move across such a fence (C). D, Associations of proteins experience more viscous force; therefore, their translational diffusion rate is usually smaller than that of monomeric proteins.
Fig. 2.
Fig. 2.
Dynamics in the hierarchical association of membrane proteins. Imaging of nanometer- and micrometer-sized protein clusters give an overview of the hierarchical association of membrane proteins. Two cell samples previously labeled with different fluorescent antibodies (green and red symbols) were fused. Lipid rafts (blue circles) are known to accumulate a specific set of proteins. Micrometer-sized protein clusters exchanged components with each other, but this process respected lipid microdomain barriers: proteins known to be in different membrane microdomains never intermixed with each other. After a lag period of ≈20 min, intermixing of nanometersized protein clusters also took place. However, this process was not as widespread as the intermixing of micrometer-sized clusters, because some proteins (e.g., MHC class II) did not show a significant ability to move from one nanometer-sized cluster to another.
Fig. 3.
Fig. 3.
Association of proteins can be induced by selective accumulation of proteins in distinct lipid microdomains (a) or by specific protein–protein interactions (b). (a) The membrane contains lipid microdomains with distinct lipid compositions. These membrane areas harbor different sets of proteins. Green lipid molecules preferentially accumulate proteins whose transmembrane domain is displayed in black and also proteins that are attached to the extracellular leaflet of the membrane (glycosylphosphatidylinositol-anchored proteins). The mechanism for the selective accumulation of proteins in a given lipid environment can be explained by a preference of proteins for the chemical (hydrophobicity) or physical (membrane thickness, microviscosity) properties of the lipid microdomain. Nanometer-sized protein associations can be considered a lipid-mediated interaction in this case. (b) Specific protein–protein interactions mediated by transmembrane proteins or ligands binding to them also may be responsible for the generation of protein associations.
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