Membrane models

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This article discusses the cell membrane models proposed from the years 1880 to
2000, which all led to the discovery of the current Fluid Mosaic Model of membranes.
For artificial membranes, see Model membrane.
Before the emergence of electron microscopy in the 1950s, scientists did not know the
structure of a cell membrane or what its components were; biologists and other
researchers used indirect evidence to identify membranes before they could actually be
visualized. Specifically, it was through the models
of Overton, Langmuir, Gorter and Grendel, and Davson and Danielli, that it was
deduced that membranes have lipids, proteins, and a bilayer. The advent of the electron
microscope, the findings of J. David Robertson, the proposal of Singer and Nicolson,
and additional work of Unwin and Henderson all contributed to the development of the
modern membrane model. However, understanding of past membrane models
elucidates present-day perception of membrane characteristics. Following intense
experimental research, the membrane models of the preceding century gave way to
the fluid mosaic model that is accepted today.

Contents

 1Gorter and Grendel's membrane theory (1920)

 2The Davson and Danielli model with backup from Robertson (1940–1960)
 3Singer and Nicolson's fluid mosaic model (1972)
 4Henderson and Unwin's membrane theory
 5See also
 6References

Gorter and Grendel's membrane theory (1920)[edit]

Diagram of the arrangement of amphipathic lipid molecules to form a lipid bi-layer. The yellow polar head
groups separate the grey hydrophobic tails from the aqueous cytosolic and extracellular environments.

Evert Gorter and François Grendel (Dutch physiologists) approached the discovery of
our present model of the plasma membrane structure as a lipid bi-layer. They simply
hypothesized that if the plasma membrane is a bi-layer, then the surface area of the
mono-layer of lipids measured would be double the surface area of the plasma
membrane. To examine their hypothesis, they performed an experiment in which they
extracted lipids from a known number of red blood cells (erythrocytes) of different
mammalian sources, such as humans, goats, sheep, etc. and then spreading the lipids
as a mono-layer in a Langmuir-Blodgett trough. They measured the total surface area of
the plasma membrane of red blood cells, and using Langmuir's method, they measured
the area of the mono-layer of lipids. In comparing the two, they calculated an estimated
ratio of 2:1 Mono-layer of lipids:Plasma membrane. This supported their hypothesis, which led to the
conclusion that cell membranes are composed of two apposing molecular layers. [1] The
two scientists proposed a structure for this bi-layer, with the polar hydrophilic heads
facing outwards towards the aqueous environment and the hydrophobic tails facing
inwards away from the aqueous surroundings on both sides of the membrane. Although
they arrived at the right conclusions, some of the experimental data were incorrect such
as the miscalculation of the area and pressure of the lipid mono-layer and the
incompleteness of lipid extraction. They also failed to describe membrane function, and
had false assumptions such as that of plasma membranes consisting of mostly lipids.
However, on the whole, this envisioning of the lipid bi-layer structure became the basic
underlying assumption for each successive refinement in modern understanding of
membrane function.[2]

The Davson and Danielli model with backup from

Robertson (1940–1960)[edit]

Trilaminar appearance of cell membrane

Following the proposal of Gorter and Grendel, doubts inevitably arose over the veracity
of having just a simple lipid bi-layer as a membrane. For instance, their model could not
provide answers to questions on surface tension, permeability, and the electric
resistance of membranes. Therefore, physiologist Hugh Davson and biologist James
Danielli suggested that membranes indeed do have proteins. According to them, the
existence of these "membrane proteins" explained that which couldn't be answered by
the Gorter-Grendel model.
In 1935, Davson and Danielli proposed that biological membranes are made up of lipid
bi-layers that are coated on both sides with thin sheets of protein and they simplified
their model into the "pauci-molecular" theory.[3] This theory declared that all biological
membranes have a "lipoid" center surrounded by mono-layers of lipid that are covered
by protein mono-layers. In short, their model was illustrated as a "sandwich" of protein-
lipid-protein. The Davson-Danielli model threw new light on the understanding of cell
membranes, by stressing the important role played by proteins in biological membranes.
By the 1950s, cell biologists verified the existence of plasma membranes through the
use of electron microscopy (which accounted for higher resolutions). J. David Robertson
used this method to propose the unit membrane model.[4] Basically, he suggested that all
cellular membranes share a similar underlying structure, the unit membrane. Using
heavy metal staining, Robertson's proposal also seemed to agree instantaneously with
the Davson-Danielli model. According to the trilaminar pattern of the cellular membrane
viewed by Robertson, he suggested that the membranes consist of a lipid bi-layer
covered on both surfaces with thin sheets of proteins. This suggestion was a great
boost to the proposal of Davson and Danielli. [5] However, even with Robertson's
substantiation, the Davson-Danielli model had serious complications, a major one being
that the proteins studied were mainly globular and couldn't therefore fit into the model's
claim of thin protein sheets. These difficulties with the model stimulated new research in
membrane organization and paved the way for the fluid mosaic model, which was
proposed in 1972.

Singer and Nicolson's fluid mosaic model (1972)[edit]

Main article: Fluid mosaic model
In 1972, S. Jonathan Singer and Garth Nicolson developed new ideas for membrane
structure. Their proposal was the fluid mosaic model, which is the dominant model now.
It has two key features—a mosaic of proteins embedded in the membrane, and the
membrane being a fluid bi-layer of lipids. The lipid bi-layer suggestion agrees with
previous models but views proteins as globular entities embedded in the layer instead of
thin sheets on the surface.
According to the model, membrane proteins are in three classes based on how they are
linked to the lipid bi-layer:

1. Integral proteins: Immersed in the bi-layer and held in place by the affinity
of hydrophobic parts of the protein for the hydrophobic tails of phospholipids on
interior of the layer.
2. Peripheral proteins: More hydrophilic, and thus are non-covalently linked to the
polar heads of phospholipids and other hydrophilic parts of other membrane
proteins on the surface of the membrane.
3. Lipid anchored proteins: Essentially hydrophilic, so, are also located on the
surface of the membrane, and are covalently attached to lipid molecules
embedded in the layer.
As for the fluid nature of the membrane, the lipid components are capable of moving
parallel to the membrane surface and are in constant motion. Many proteins are also
capable of that motion within the membrane. However, some are restricted in their
mobility due to them being anchored to structural elements such as the cytoskeleton on
either side of the membrane.
In general, this model explains most of the criticisms of the Davson–Danielli model. It
eliminated the need to accommodate membrane proteins in thin surface layers,
proposed that the variability in the protein/lipid ratios of different membranes simply
means that different membranes vary in the amount of protein they contain, and showed
how the exposure of lipid-head groups at the membrane surface is compatible with their
sensitivity to phospholipase digestion. Also, the fluidity of the lipid bi-layers and the
intermingling of their components within the membrane make it easy to visualize the
mobility of both lipids and proteins.

Singer and Nicolson's fluid mosaic model

Henderson and Unwin's membrane theory[edit]

Transient receptor potential cation channel subfamily V member 1 (TRPV1). Ion channels are integral
membrane proteins of great importance for living organisms.

Henderson and Unwin have studied the purple membrane by electron microscopy,

using a method for determining the projected structures of unstained crystalline
specimens. By applying the method to tilted specimens, and using the principles put
forward by DeRosier and Klug for the combination of such two-dimensional views, they
obtained a 3-dimensional map of the membrane at 7 Å resolution. The map reveals the
location of the protein and lipid components, the arrangement of the polypeptide chains
within each protein molecule, and the relationship of the protein molecules in the lattice.
[6]

High-resolution micrographs of crystalline arrays of membrane proteins, taken at a low

dose of electrons to minimize radiation damage, have been exploited to determine the
three-dimensional structure by a Fourier transform. Recent studies on negatively
stained rat hepatocyte Gap™ junctions subjected to 3-dimensional Fourier
reconstructions (of low-dose electron micrographs) indicate that the six protein sub-units
are arranged in a cylinder slightly tilted tangentially, enclosing a channel 2 nm wide at
the extracellular region. The dimensions of the channel within the membrane were
narrower but could not be resolved (Unwin and Zampighi, 1980). A small radical
movement of the sub-units at the cytoplasmic ends could reduce the sub-unit inclination
tangential to six-fold axis and close the channel. [7]
Further details of the molecular organization should emerge as more methods of
preparation become available, so that high-resolution 3-dimensional images
comparable to the purple membranes are obtained. By using ingenious procedures for
the analysis of periodic arrays of biological macromolecules, in which data from low-
dose electron images and diffraction patterns were combined, Henderson and Unwin
(1975) reconstructed a three-dimensional image of purple membranes at 0.7 nm
resolution. Glucose embedding was employed to alleviate dehydration damage and low
doses (< 0.5 e/A*) to reduce the irradiation damage. The electron micrographs of
unstained membranes were recorded such that the only source of contrast was a weak
phase contrast induced by defocusing.
In their experiment, Unwin and Henderson found that protein extends to both sides of
the lipid bi-layer and is composed of seven α-helices packed about 1–1.2 nm apart, 3.5–
4.0 nm in length, running perpendicular to the plane of membrane. The molecules are
organized around a 3-fold axis with a 2 nm-wide space at the center that is filled with
lipids. This elegant work represents the most significant step forward thus far, as it has
for the first time provided us with the structure of an integral membrane protein in situ.
The availability of the amino acid sequence, together with information about the electron
scattering density from the work of Henderson and Unwin, has stimulated model-
building efforts (Engleman et al., 1980) to fit the bacteriorhodopsin sequence
information into a series of α-helical segments.