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Cover Thirty years ago, Frye and Edidin demonstrated "the rapid intermixing of cell surface antigens after formation of mouse-human heterokaryons" (1970, J. Cell. Sci. 7, 319-335). The authors inferred that at least some membrane proteins are free to diffuse in plane and are therefore likely to be dissolved in the bilayer. The report appeared at a time of explosive innovation in membrane research, when the inquiry into membrane organization was seething with uncertainty, skepticism, and debate (see, for example, Korn [1969], Annu Rev Biochem. 38, 263-288). The debate focused on whether continuous lipid bilayers were the central element in biomembrane organization, and the disposition of membrane proteins was obscure (Stoeckenius and Engelman, 1969, J. Cell. Biol. 42, 613-646). It was understood at that time that numerous protein species were associated with membranes, that many of these were insoluble in water and might contact the hydrophobic core of the bilayer, and that such proteins might comprise the intramembrane particles visualized by freeze-fracture electron microscopy. It was also appreciated that a variety of membrane functions (such as chemiosmotic energy metabolism, the electrical excitability of neurons, and the transduction of peptide hormone signals) might be mediated by membrane-spanning proteins. Nevertheless, the reigning model of biomembranes was the protein-coated bilayerthe Danielli trilaminar sandwich.

By the late 1960s, a variety of physical techniques had documented the free lateral diffusion of membrane lipids. If the core of the membrane were a fluid with the viscosity of a light oil, proteins dissolved therein should also translate rapidly and randomly in plane. Dramatic evidence to this effect emerged in 1969 from the low angle X-ray scattering of rhodopsin in retinal disk membranes (Blasie and Worthington, 1969, J. Mol. Biol. 39, 417-439). This penetrating study was not immediately appreciated, however.

In 1970, Frye and Edidin fused mouse and human cells and followed by immunofluorescence the redistribution of antigens on the surface of the resulting hybrids (see Cover). They first showed that in established hybrid cells"infinite time" controlsboth the mouse (green; panel A) and the human (red; panel B) surface antigens were in circumferential rings, hence, more or less uniformly distributed. In contrast, these antigens were located in separate hemispherical poles when viewed immediately after fusion (panel C). The redistribution of these proteins then proceeded briskly, with the mouse antigen (panel D) moving somewhat more slowly than its human counterpart (panel E). Within 40 min, both markers covered the entire surface of almost every fused cell pair (panels F and G). That the proteins diffused freely in a fluid phospholipid bilayer was inferred from a simple kinetic analysis and from the complete arrest of antigen redistribution below 15°C.

As the authors were careful to point out, this simple study was not definitive. But it did open the door wide. In the decade that followed, evidence rapidly accumulated that many membrane proteins are integral to and mobile within the bilayer. And where the mobility of the integral proteins is constrained, mechanisms of tethering, sorting, and sequestration were uncovered. The physical and functional ramifications of membrane protein mobility are vast, making the Frye and Edidin paradigm integral to molecular cell biology.

This figure is reproduced from the Journal of Cell Science, 1970, 7, 319-335, with copyright permission.Ted Steck