The lipid bilayer membrane and its protein constituents

Abstract

In 1918, the year the Journal of General Physiology was founded, there was little understanding of the structure of the cell membrane. It was evident that cells had invisible barriers separating the cytoplasm from the external solution. However, it would take decades before lipid bilayers were identified as the essential constituent of membranes. It would take even longer before it was accepted that there existed hydrophobic proteins that were embedded within the membrane and that these proteins were responsible for selective permeability in cells. With a combination of intuitive experiments and quantitative thinking, the last century of cell membrane research has led us to a molecular understanding of the structure of the membrane, as well as many of the proteins embedded within. Now, research is turning toward a physical understanding of the reactions of membrane proteins and lipids in this unique and incredibly complex solvent environment.

Figure 1.

Plasmolysis reveals invisible barriers within living cells. (A and B) A normal Spirogyra cell (A) and the cell during plasmolysis (B). From Overton (1895), Fig. 1 is adapted from Vierteljahresschr. Naturforsch. Ges. Zürich.

Figure 2.

A brief history of cellular barriers. (A) The protoplasmic colloid model. The barrier is a hardened shell that forms when the dense colloidal protoplasm makes contact with the extracellular solution. Pictured here is artificial caviar made by the analogous process of spherification. Photo courtesy of J.L. Robertson. (B) The paucimolecular model of Davson and Danielli, where the cell barrier is modeled as a lipid bilayer with a lipoid core flanked by layers of polar and charged proteins. From Danielli and Davson (1935), Fig. 2 B is adapted with permission from the Journal of Cellular Physiology. (C) The unit membrane model of Robertson, indicating the train track–appearing lipid bilayer that forms a continuous membrane around the cell. From Robertson (1981), Fig. 2 C is adapted with permission from the Journal of Cell Biology. (D) The fluid mosaic model of Singer and Nicolson, showing a lipid bilayer with integral membrane proteins responsible for cellular permeability. From Singer and Nicolson (1972), Fig. 2 D is adapted with permission from Science.

Figure 3.

The Meyer–Overton correlation. Anesthetic efficacy in a clinical setting correlates strongly with the partitioning ratio of a compound from the gas state into olive oil. Their findings suggested that cell membranes are also lipoid in nature. From Campagna et al. (2003), Fig. 3 is adapted with permission from the New England Journal of Medicine.

Figure 4.

Electrical reconstitution of membrane permeability. (A) The BLM preparation for electrical measurements of permeability, adapted from Tien (1968). (B) The first single-channel recording of Gramicidin in lipid bilayers. From Hladky and Haydon (1970), Fig. 4 is adapted with permission from Nature.

Figure 5.

Structural evidence of lipids interacting with membrane proteins. From left to right, a POPG molecule bound to the K⁺ channel KcsA (Valiyaveetil et al., 2002), lipids bound to the interface of a single monomer of the water channel Aqp0 (Hite et al., 2010), and a ring of lipids resolved in the x-ray crystal structure of the Ca²⁺-ATPase by phase contrast imaging (Norimatsu et al., 2017).

Figure 6.

Membrane protein stability depends on membrane energetics. The lipid bilayer is a macroscopic material with elastic properties that affect membrane protein conformational stability and assembly. Membrane deformations have been shown to affect Gramicidin dimer equilibrium (A); ion channel gating (B), adapted from Lundbaek et al. (2004); and long-range assembly of ATP synthase dimers during the formation of cristae (C), from Anselmi et al. (2018), adapted with permission from J. Gen. Physiol.

Figure 7.

Insertion and assembly of α-helical membrane proteins in membranes. (A and B) Membrane protein folding follows the two-stage model (Popot and Engelman, 1990) involving synthesis and partitioning into the lipid bilayer, facilitated by insertases such as the translocon in cells (A), followed by the association of helices into the biological folded structure (B). Image of ribosome from Goodsell (2010), adapted from The Protein Data Bank. (C) Association of subunits or single helices provides a simplified model for studying the thermodynamics of membrane protein association in membranes.