CHAPTER 7 Membrane Structure and Dynamics
Membranes composed of lipids and proteins form the barrier between each cell and its environment. Membranes also partition the cytoplasm of eukaryotes into compartments, including the nucleus and membrane-bounded organelles. Each type of membrane is specialized for its various functions, but all biological membranes have much in common: a planar fluid bilayer of lipid molecules, integral membrane proteins that cross the lipid bilayer, and peripheral membrane proteins on both surfaces.
This chapter opens with a discussion of the lipid bilayer. It then considers examples of integral and peripheral membrane proteins before concluding with a discussion of the dynamics of both lipids and proteins. The following three chapters introduce three large families of membrane proteins: pumps, carriers, and channels. Chapter 11 explains how pumps, carriers, and channels cooperate in a variety of physiological processes. Chapters 24 and 30 cover plasma membrane receptor proteins.
Development of Ideas about Membrane Structure
Our current understanding of membrane structure began with E. Overton’s proposal in 1895 that cellular membranes consist of lipid bilayers (Fig. 7-1A). Biochemical experiments in the 1920s supported the bilayer hypothesis. It was found that the lipids extracted from the plasma membrane of red blood cells spread out in a monolayer on the surface of a tray of water to cover an area sufficient to surround the cell twice. (Actually, offsetting errors—incomplete lipid extraction and an underestimation of the membrane area—led to the correct answer!) X-ray diffraction experiments in the early 1970s established definitely that membrane lipids are arranged in a bilayer.
Figure 7-1 development of concepts in membrane structure. A, Gorder and Grendel model from 1926. B, Davson and Danielli model from 1943. C, Singer and Nicholson fluid mosaic model from 1972. D, Contemporary model with peripheral and integral membrane proteins. The lipid bilayer shown here and used throughout the book is based on an atomic model (Fig. 7-5).
During the 1930s, cell physiologists realized that a simple lipid bilayer could not explain the mechanical properties of the plasma membrane, so they postulated a surface coating of proteins to reinforce the bilayer (Fig. 7-1B). Early electron micrographs strengthened this view, since when viewed in cross sections, all membranes appeared as a pair of dark lines (interpreted as surface proteins and carbohydrates) separated by a lucent area (interpreted as the lipid bilayer). By the early 1970s, two complementary approaches showed that proteins cross the lipid bilayer. First, electron micrographs of membranes that are split in two while frozen (a technique called freeze-fracturing; see Fig. 6-4D) revealed protein particles embedded in the lipid bilayer. Later, chemical labeling showed that many membrane proteins traverse the bilayer, exposing different regions of the polypeptide to the aqueous phase on the two sides. Light microscopy with fluorescent tags demonstrated that membrane lipids and some membrane proteins diffuse in the plane of the membrane. Quantitative spectroscopic studies showed that lateral diffusion of lipids is a rapid process but that flipping from one side of a bilayer to the other is a slow one. The fluid mosaic model of membranes (Fig. 7-1C) incorporated this information, showing transmembrane proteins floating in a fluid lipid bilayer. Subsequent work revealed structures of many proteins that span the lipid bilayer, the existence of lipid anchors on some membrane proteins, and a network of cytoplasmic proteins that restricts the motion of many integral membrane proteins (Fig. 7-1D).
Lipids
This chapter concentrates on major lipids found in biological membranes. After an introduction to their structures, the following section explains how the hydrophobic effect drives lipids to self-assemble stable bilayers. Membranes also contain hundreds of minor lipids, some of which might have important biological functions that are not yet appreciated. For example, during the 1980s, a minor class of lipids with phosphorylated inositol head groups first attracted attention when investigators found that they had a major role in signaling (see Fig. 26-7).
Phosphoglycerides
Phosphoglycerides (also called glycerolphospholipids) are the main constituents of membrane bilayers (Fig. 7-2). (These lipids are often called phospholipids, an imprecise term, as other lipids contain phosphate.) Phosphoglycerides have three parts: a three-carbon back-bone of glycerol, two long-chain fatty acids esterified to carbons 1 and 2 (C1 and C2) of the glycerol, and phosphoric acid esterified to C3 of the glycerol. Fatty acids have a carboxyl group at one end of an aliphatic chain of 13 to 19 additional carbons (Table 7-1). More than half of the fatty acids in membranes have one or more double bonds, which create a bend in the aliphatic chain. These bends contribute to the fluidity of the bilayer. Fatty acids and phosphoglycerides are amphiphilic, since they have both hydrophobic (fears water) and hydrophilic (loves water) parts. The aliphatic chains of fatty acids are hydrophobic. The carboxyl groups of fatty acids and the head groups of phosphoglycerides are hydrophilic. The cross-sectional areas of the head groups and the aliphatic tails are similar, so a phosphoglyceride is shaped approximately like a cylinder—an important factor in membrane structure. The hydrophobic effect (see Fig. 4-5) drives amphiphilic phosphoglycerides to assemble bilayers (see later).
| Name | Carbons | Double Bonds (Positions) |
|---|---|---|
| Myristate | 14 | 0 |
| Palmitate | 16 | 0 |
| Palmitoleate | 16 | 1 (Δ9) |
| Stearate | 18 | 0 |
| Oleate | 18 | 1 (Δ9) |
| Linoleate | 18 | 2 (Δ9, Δ12) |
| Linolenate | 18 | 3 (Δ9, Δ12, Δ15) |
| Arachidonate | 20 | 4 (Δ5, Δ8, Δ11, Δ14) |
The several head groups confer distinctive properties to the various phosphoglycerides. All have a negative charge on the phosphate esterified to glycerol. Neutral phosphoglycerides—PE and PC—have a positive charge on their nitrogens, giving them a net charge of zero. PS has extra positive and negative charges, giving it a net negative charge like the other acidic phosphoglycerides (PA, PG, and PI). PI can be modified by esterifying one to five phosphates to the hexane ring hydroxyls. These polyphosphoinositides are highly negatively charged.
Several minor membrane phospholipids are variations on this general theme. Plasmalogens have a fatty acid linked to carbon 1 of glycerol by an ether bond rather than an ester bond. They serve as sources of arachidonic acid for signaling reactions (see Fig. 26-9). Cardiolipin has two glycerols esterified to the phosphate of PA.
Sphingolipids
Most sugar-containing lipids of biological membranes are sphingolipids. Sphingolipids get their name from sphingosine, a nitrogen-containing base (Fig. 7-3) that is the structural counterpart of glycerol and one fatty acid of phosphoglycerides. Sphingosine carbons 1 to 3 have polar substituents. A double bond between C4 and C5 begins the hydrocarbon tail. Two variable features distinguish the various sphingolipids: the fatty acid (often lacking double bonds) attached by an amide bond to C2 and the nature of the polar head groups esterified to the hydroxyl on C1.
The head groups of glycosphingolipids consist of one or more sugars. Some are neutral; others are negatively charged. Note the absence of phosphate. Sugar head groups of some glycosphingolipids serve as receptors for viruses. Alternatively, a phosphate ester can link a base to C1. These so-called sphingomyelins have phosphorylcholine or phosphoethanolamine head groups just like PC and PE. Receptor-activated enzymes remove phosphorylcholine from sphingomyelin to produce the second messenger ceramide (see Fig. 26-11). Sphingolipids are much more abundant in the plasma membrane than in membranes inside cells. The hydrocarbon tails of sphingosine and the fatty acid contribute to the hydrophobic bilayer, and polar head groups are on the surface.
Sterols
Sterols are the third major class of membrane lipids. Cholesterol (Fig. 7-4) is the major sterol in animal plasma membranes, with lower concentrations in internal membranes. Plants, lower eukaryotes, and bacteria have other sterols in their membranes. The rigid four-ring structure of cholesterol is apolar, so it inserts into the core of bilayers with the hydroxyl on C3 oriented toward the surface.
Cholesterol is vital to metabolism, being situated at the crossroads of several metabolic pathways, including those that synthesize steroid hormones (such as estrogen, testosterone, and cortisol), vitamin D, and bile salts secreted by the liver. Cholesterol itself is synthesized (see Fig. 20-13) from isopentyl (5-carbon) building blocks that form 10-carbon (geranyl), 15-carbon (farnesyl), and 20-carbon (geranylgeranyl) isoprenoids. As is described later, these isoprenoids are used as hydrocarbon anchors for many important membrane-associated proteins. Isoprenoids are also precursors of natural rubber and of cofactors present in visual pigments.
Glycolipids
Cells have three types of glycolipids: (1) sphingolipids (the predominant form), (2) glycerol glycolipids with sugar chains attached to the hydroxyl on C3 of diglycerides, and (3) glycosylphosphatidylinositols (GPI). Some glycosylphosphatidylinositols simply have a short carbohydrate chain on the hydroxyl of inositol C2. Others use a short sugar chain to link C6 of phosphatidylinositol to the C-terminus of a protein (Fig. 7-9C).
Triglycerides
Triglycerides are simply glycerol with fatty acids esterified to all three carbons. Lacking a polar head group, they are not incorporated into membrane bilayers. Instead, triglycerides form large, oily droplets in the cytoplasm that are a convenient way to store fatty acids as reserves of metabolic energy. In white adipose cells, specialized for lipid storage, the triglyceride droplet occupies most of the cytoplasm (see Fig. 28-6). Mitochondria oxidize fatty acids and convert the energy in their covalent bonds into ATP (see Fig. 19-4).
Physical Structure of the Fluid Membrane Bilayer
In an aqueous environment, amphiphilic lipids spontaneously self-assemble into ordered structures in microseconds. The cylindrical shapes and amphiphilic nature of phosphoglycerides and sphingolipids favor formation of lamellar bilayers, planar structures with fatty acid chains lined up more or less normal to the surface and polar head groups on the surfaces exposed to water (Fig. 7-1D). Bilayer formation is energetically favorable, owing to the increase in entropy when the hydrophobic acyl chains interact with each other and exclude water from the core of the bilayer. This hydrophobic effect increases the entropy of the system and drives the assembly process.
An atomic model of a phosphoglyceride bilayer (Fig. 7-5
