Two broad models for the relationship between membrane proteins and the lipid bilayer
As I noted in an earlier post, cell membranes are composed mostly of lipids (primarily phospholipids) and some protein. The question is how are the proteins arranged relative to the bilayer of phospholipids? Over the years, there were two broad models of membrane structure. In a 1969 review, Stoeckenius and Engelman identified them as the Danielli (or bilayer) model and the Subunit model. The Danielli model was an extension of the lipid bilayer hypothesis proposed by Gorter & Grendel. The model attempted to incorporate membrane proteins into the idea of a lipid bilayer by proposing that there would be layers of protein associated with the inside and outside of the bilayers (Danielli and Davson, 1935). This was sometimes referred to as the “protein sandwich” model, with the lipid bilayer sandwiched between two layers of protein. In the figure below (taken from Danielli & Davson’s 1935 paper), the spheres represent proteins and the rectangles topped with half circles are phospholipids. I’m not really that clear on Danielli’s evidence for this model – he refers to other research he conducted saying, “…in a number of egg cells proteins are present of such a surface activity such that an adsorbed layer [of proteins] is bound to be present…”
The subunit model seems to have grown out of discoveries related to the protein coats of viruses. According to Stoeckenius & Engelman, the exact nature of the subunit was never clearly defined. Apparently, it was assumed to be some combination of lipids and proteins stuck together to form repeating modular structures, so they were referred to as lipoprotein subunits. It’s not clear to me that the subunit model was incompatible with the idea of a lipid bilayer, but it probably was incompatible with the notion of a protein sandwich. One example of a subunit model (shown below) was given by Benson (1966). Notice that his model has a bilayer with a protein woven in amongst the lipids. Perhaps I’m projecting onto this something that Benson did not intend, but he seems as close to the currently accepted structure as Danielli was. At least he recognized that the proteins were in the bilayer. On the other hand, the idea that membranes were composed of self-assembling lipoprotein subunits was incorrect.
[A portion of Figure 4 from Benson (1966) Journal of the American Oil Chemists’ Society 42: 265-270; click figure for larger image.]
From a sandwich to a mosaic
By the mid-1960s, a number of researchers were clearly unsatisfied with the protein sandwich. In 1966, the Proceedings of the National Academy of Sciences (USA) published similar studies by Wallach & Zahler and Lenard & Singer. Both studies used spectroscopic methods (including infrared spectra, fluorescence spectra and optical rotator dispersion) to examine the shape of proteins associated with cell membranes. Without getting in over my head, the basic idea of all spectroscopic methods is to shine electromagnetic radiation (such as visible light or infrared radiation) at something and analyze the pattern of radiation absorbed or transmitted. Different types of radiation provide different ways of “seeing” a molecule. In this case, the scientists found particular structures in the proteins that suggested extensive interaction between hydrophobic parts of proteins with the hydrophobic parts of lipids in the bilayer. This implied that parts of proteins were in the bilayer. Both groups of researchers explicitly recognized that this contradicted the “protein sandwich” model of membrane structure. Continuing spectroscopic work (Glaser and colleagues, 1970) led to the suggestion that most of the lipids in a membrane weren’t interacting with proteins. As a result, the researchers envisioned membranes as having “a mosaic pattern…In this scheme, globular protein molecules…are interspersed in a matrix consisting of the remaining lipids in a form similar to that of a discontinuous bilayer.” They provided a schematic drawing of this vision (see below). Today, we might summarize this by saying that islands of protein float in a sea of lipids.
Benson, A.A. (1966) “On the orientation of lipids in chloroplast and cell membranes.” Journal of the American Oil Chemists’ Society 42: 265-270
Danielli, J.F. and Davson, H. (1935) “A contribution to the theory of permeability of thin films.” Journal of Cellular and Comparative Physiology 5: 495-507
Glaser, M., Simpkins, H., Singer, S.J., Sheetz, M., and Chan, S.I. (1970) “On the interactions of lipids and proteins in the red blood cell membrane.” PNAS 65(3): 721-8
Gorter, E. and Grendel, F. (1925) “On bimolecular layers of lipoids on the chromocytes of the blood.” Journal of Experimental Medicine 41: 439-443
Lenard, J. and Singer, S.J. (1966) “Protein conformation in cell membrane preparations as studied by optical rotatory dispersion and circular dichroism.” PNAS 56(6): 1828-1835
Stoeckenius, W. and Engelman, D.M. (1969) “Current models for the structure of biological membranes.” Journal of Cell Biology 42: 613-646
Wallach, D.F.H. and Zahler, P.H. (1966) “Protein conformations in cellular membranes.” PNAS 56(5): 1552-9 [http://www.pnas.org/content/56/5/1552.full.pdf]