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CRC Press
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Contents
Preface..............................................................................................................................................vii
Editor.................................................................................................................................................ix
Contributors.......................................................................................................................................xi

Chapter 1 Introduction to Lipid Bilayers.......................................................................................1

Philip L. Yeagle

Chapter 2 Membrane Proteins....................................................................................................... 7

Philip L. Yeagle

Chapter 3 Introduction to Lipid–Protein Interactions in Biological Membranes........................ 13

Philip L. Yeagle

Chapter 4 The Mesomorphic Phase Behavior of Lipid Bilayers................................................. 19

Ruthven N.A.H. Lewis and Ronald N. McElhaney

Chapter 5 IR Spectroscopy of Lipid Chains: Theoretical Background and Applications

to Phase Transitions, Membranes, Cells, and Tissues................................................. 91
Richard Mendelsohn

Chapter 6 The Roles of Cholesterol in the Biology of Cells...................................................... 119

Philip L. Yeagle

Chapter 7 Functional Consequences of the Lateral Organization of Biological Membranes..... 133

Richard M. Epand and Raquel F. Epand

Chapter 8 Mechanisms by Which Pathogens Hijack and Utilize Membrane Domains to

Mediate Cytotoxicity................................................................................................. 153
Claude Krummenacher, Angela C. Brown, Thomas Edrington V,
Bruce J. Shenker, and Kathleen Boesze-Battaglia

Chapter 9 Lipid-Assisted Membrane Protein Folding and Topogenesis.................................... 177

William Dowhan and Mikhail Bogdanov

Chapter 10 Membrane Protein Biogenesis and Assembly at the Endoplasmic Reticulum

Membrane.................................................................................................................. 203
Meera K. Bhanu and Debra A. Kendall

v
vi Contents

Chapter 11 Thermal Denaturation of Membrane Proteins.......................................................... 223

Arlene D. Albert

Chapter 12 Mass Action Kinetic Analysis of Multidrug Resistance Transporters Expressed

in Confluent Cell Monolayers.................................................................................... 241
Annie Albin Lumen, Deborah Silverman, Esteban Martinez, Zeba Ahmed,
Deep Agnani, Poulomi Acharya, and Joe Bentz

Chapter 13 How to Understand Lipid–Protein Interactions in Biological Membranes............... 273

Anthony G. Lee

Chapter 14 Biogenesis of Lipids and Proteins within Mitochondrial Membranes...................... 315

Nathan Alder
Preface
The study of biological membranes is much younger than many today may suspect and yet the field
has rapidly progressed to encompass the incredible complexity of cell and viral membranes. Prior to
the 1970s, researchers struggled to describe the fundamental architecture of biological membranes
(the authors of Chapter 4 played a central role by extending the concept of the lipid bilayer from
model membranes to intact biological membranes). When the 1970s arrived with a firm view of the
lipid bilayer as the fundamental structural feature of both model and biological membranes, the field
of membrane studies exploded with a wealth of creativity in concepts and experimental designs (a
number of the authors were chosen for this book because of the scope of the history of the field they
could bring to a discussion of contemporary membrane studies). The result was a rapid advance in
understanding both structure and function of artificial and biological membranes, a very specialized
world that is nearly two dimensional and lies at the center of all cellular and viral function.
Because much of what happens in a cell or in a virus occurs on, in, and/or across biological mem-
branes, the study of biological membranes rapidly penetrated many fields of biology, pharmaceuti-
cal chemistry, and materials science. The diffusion of the field has perhaps created a diminution of
the connection to the fundamentals of membrane structure that still inform new experiments and
new understandings today. The purpose of this book, therefore, is to make available to students of
membranes, understandings rooted in the history of the field and brought to the forefront of our cur-
rent knowledge by experts in a variety of fields.
Many faculty members have brought to my attention that the two previous editions of this book
have been used in many classrooms at a number of universities. The totality of the content of the
previous editions would have been very challenging to the student new to the field. Therefore, I
have provided three chapters (Chapters 1 through 3) in this third edition to introduce the student to
the fundamentals of membrane structure and to provide the tools and conceptual framework with
which to approach the state-of-the-art chapters that follow. The emphasis in these chapters is on the
fundamentals of lipid bilayers and membrane proteins.
Three chapters follow (Chapters 4 through 6) with an emphasis on the lipid bilayer of biological
membranes. Chapter 4 provides up-to-date insight into the phase behavior of lipid bilayers, manifest
because lipid bilayers are a (nearly) two-dimensional ordered matrix that can exist in more than
one phase structure. FTIR provides detailed information on the internal structure and dynamics of
membrane lipids, and Chapter 5 provides a view of lipid bilayers as an isolated structure and in a
surprising variety of biological contexts. Chapter 6 focuses on a lipid component that has attracted
intense interest over the years because of its myriad influences on membrane structure and biologi-
cal function—cholesterol.
The next two chapters (Chapters 7 and 8) explore the lateral organization of membranes, which
display an inhomogeneous distribution of lipid components (and protein components in biologi-
cal membranes) in the plane of the membrane driven in part by lipid properties (introduced in
Chapter 4).
The remaining six chapters (Chapters 9 through 14) focus on the protein component of the bio-
logical membranes. Chapter 9 examines the role that membrane lipids play in initial membrane
protein folding. Chapter 10 discusses current understandings of membrane protein synthesis and
assembly of oligomeric membrane proteins. Chapter 11 describes a new view of membrane protein
stability with relationships to function and protein turnover. Chapter 12 provides insight into mem-
brane protein function using a transport protein. In Chapter 13, interactions between membrane
proteins and membrane lipids, the two major components of biological membranes, are examined—
interactions that have a large role in membrane function. Finally, Chapter 14 pulls together many of

vii
viii Preface

the above topics, examining in detail the complexity inherent in the synthesis and assembly of lipids
and proteins in mitochondrial membranes.
I thank each of the authors who have contributed to this volume and dedicate this collective effort
to the students who read it. I thank the staff of CRC Press who have worked hard in support of this
project to bring it to reality.
Editor
Philip L. Yeagle, a national merit finalist, graduated from St. Olaf College, Minnesota (magna cum
laude with honors in chemistry) in 1971, having spent two terms at the University of Cambridge.
He obtained his PhD at Duke University in 1974, studying enzyme structure and function, sup-
ported by an NDEA predoctoral fellowship. As a postdoctoral fellow at the University of Virginia,
he started his studies of membrane structure and dynamics, supported by an NIH postdoctoral fel-
lowship. There he was one of the first investigators to discover and exploit the opportunities for 31P
NMR studies of model and biological membranes. Dr. Yeagle began his faculty career in the School
of Medicine, University at Buffalo, supported by an NIH Research Career Development Award
(RCDA), during which time he was able to define the molecular basis of an essential role of cho-
lesterol in mammalian cell membranes. In 1985, he was a visiting scientist at the Commonwealth
Scientific and Industrial Research Organisation (CSIRO), New South Wales, Australia, and in 1988
he developed the first in a series of FASEB Summer Research Conferences on membrane struc-
ture. In 1993, and again in 2003, he was a visiting professor in the Department of Biochemistry,
University of Oxford. He moved in 1997 to the Department of Molecular and Cell Biology at the
University of Connecticut as head of department and pursued studies of membrane protein struc-
ture. He was elected member of the Council of the Biophysical Society and chair of the Membrane
Structure and Assembly subgroup that he helped form. He was executive editor of Biochemica et
Biophysica Acta Biomembranes for a decade, a member of the editorial board of the Journal of
Biological Chemistry, published over 150 papers and reviews, and is the author or editor of 7 books.
In 2007, he accepted the position of dean of the Faculty of Arts and Sciences and chief academic
research officer at Rutgers University, Newark, New Jersey.

ix
Contributors
Poulomi Acharya Mikhail Bogdanov
Department of Biology Department of Biochemistry and Molecular
Drexel University Biology
Philadelphia, Pennsylvania University of Texas Medical School at Houston
Houston, Texas
Deep Agnani
Department of Biology Angela Brown
Drexel University Department of Pathology
Philadelphia, Pennsylvania School of Dental Medicine
University of Pennsylvania
Philadelphia, Pennsylvania
Zeba Ahmed
Department of Biology
William Dowhan
Drexel University
Department of Biochemistry and Molecular
Philadelphia, Pennsylvania
Biology
University of Texas Medical School at Houston
Arlene D. Albert Houston, Texas
Department of Molecular and Cell Biology
University of Connecticut Thomas Edrington V
Storrs, Connecticut Department of Molecular Physiology and
Biological Physics
Nathan Alder University of Virginia Health Science Center
Department of Molecular and Cell Biology Charlottesville, Virginia
University of Connecticut
Storrs, Connecticut Raquel F. Epand
Department of Biochemistry & Biomedical
Sciences
Joe Bentz
Department of Biology Health Science Center
McMaster University
Drexel University
Hamilton, Ontario, Canada
Philadelphia, Pennsylvania

Richard M. Epand
Meera K. Bhanu Department of Biochemistry & Biomedical
Department of Molecular and Cell Biology Sciences
University of Connecticut Health Science Center
Storrs, Connecticut McMaster University
Hamilton, Ontario, Canada
Kathleen Boesze-Battaglia
Department of Biochemistry Debra A. Kendall
School of Dental Medicine Department of Pharmaceutical Sciences
University of Pennsylvania University of Connecticut
Philadelphia, Pennsylvania Storrs, Connecticut

xi
xii Contributors

Claude Krummenacher Ronald N. McElhaney

Department of Biochemistry Faculty of Medicine and Dentistry
School of Dental Medicine Department of Biochemistry
University of Pennsylvania School of Molecular and Systems Medicine
Philadelphia, Pennsylvania University of Alberta
Edmonton, Alberta, Canada
Anthony G. Lee
Richard Mendelsohn
School of Biological Sciences
Department of Chemistry
University of Southampton
Newark College of Arts and Sciences
Southampton, United Kingdom
Rutgers University
Newark, New Jersey
Ruthven N.A.H. Lewis
Faculty of Medicine and Dentistry Bruce J. Shenker
Department of Biochemistry Department of Pathology
School of Molecular and Systems Medicine School of Dental Medicine
University of Alberta University of Pennsylvania
Edmonton, Alberta, Canada Philadelphia, Pennsylvania

Deborah Silverman
Annie Albin Lumen
Department of Biology
Department of Biology
Drexel University
Drexel University
Philadelphia, Pennsylvania
Philadelphia, Pennsylvania
Philip L. Yeagle
Esteban Martinez Faculty of Arts & Sciences
Department of Biology Office of the Dean
Drexel University Rutgers University
Philadelphia, Pennsylvania Newark, New Jersey
 1 Introduction to Lipid Bilayers
Philip L. Yeagle

CONTENTS
Lipid Bilayer....................................................................................................................................... 1
Lipid Bilayer Properties...................................................................................................................... 3
References........................................................................................................................................... 6

The membranes of cells and viruses are the fundamental architecture upon which both function
and structure of these biological entities are built. All cells and some viruses are bounded by a
membrane, providing the definition of the outer extremities of the cell or virus. Membranes provide
fundamental compartmentalization, creating a distinction between the inside and outside of a cell
or a virus. Compartmentalization provides an opportunity for differentiation of the inside from
the outside of the cell, creating a key opportunity for development in the evolution of the most
primitive forms of life. In addition to the bounding function, the exterior membrane must provide
communication between inside and outside and the ability to move molecules (“food and wastes”)
selectively from the inside to the outside and from the outside to the inside of the cell. In eukaryotic
cells, membranes provide complexity in structure and differentiated function through intracellular
organelles that are each constructed of unique membranes, differing in composition and function
from the plasma membrane and from each other. In many cases, the membrane architecture pro-
vides biological functions uniquely derived from that structure in addition to compartmentalization
of intracellular function.
These and a myriad of other structures and functions of cells and viruses derive from the
molecular composition, with both the individual and aggregate properties deriving from the
membrane molecular components. It is worthwhile to review how these molecular components
and their individual properties can lead to the structures and functions exhibited by biological
membranes.

LIPID BILAYER
The fundamental structural component of all biological membranes, whether cell membranes or
viral membranes, is the lipid bilayer. The lipid bilayer consists of two opposed layers of amphipathic
lipid molecules, hydrophilic headgroups directed outwards and encountering the aqueous phase,
and hydrophobic tails sequestered in the interior of the two layers in direct contact with each other
(see Figure 1.1). The lipid bilayer derives its structure from the chemistry of the membrane lipids.
Cell membrane lipids are for the most part, amphipathic molecules. Usually two (but sometimes
one or four or more) long hydrocarbon chains are bonded to the polar headgroup. This molecu-
lar structure offers a hydrophobic portion of the molecule (the hydrocarbon chains) that must be
sequestered from water and a hydrophilic portion (the polar headgroup that may have negative and
or positive charges and hydrogen-bonding chemical structures) that interacts effectively with the
hydrogen-bonding network of the water. Because of the dominant nature of the hydrophobic portion

1
2 The Structure of Biological Membranes

of the molecule, many membrane lipids have notoriously low solubility

in water (e.g., cholesterol has nanomolar solubility in water while a typi-
cal phospholipid will have its solubility limited to about 10 −14 M).
When the molecular cross-section of the lipid headgroup is similar
to the molecular cross-section of the hydrocarbon region, the entire FIGURE 1.1 Schematic
molecule can be approximated as a cylinder. In aqueous medium, these representation of the lipid
cylinders spontaneously pack side-by side such that the hydrophobic bilayer.
regions are in intimate contact and the polar portions encounter the
aqueous phase. Simply opposing two layers of lipids packed in this man-
ner (with the hydrocarbon ends of the cylinders in contact) creates the
lipid bilayer and sequesters the hydrophobic portions from the aqueous
media (Figure 1.2).
The lipid bilayer is properly imaged as an extended, nearly two-
dimensional structure stabilized by non-covalent forces (driven by the
hydrophobic effect) that are sufficiently strong to maintain the integrity FIGURE 1.2 Packing of
of both compartmentalization and enzymatic functions. As such the cylinders to produce a lipid
lipid bilayer exhibits unique properties that are exploited by biology for bilayer.
function.
The lipid bilayer forms spontaneously from amphipathic lipids in aqueous media. No special cel-
lular apparatus is required to assemble the lipid bilayer. In most cases, simply introducing purified
membrane lipids into an aqueous medium will result in the formation of lipid bilayers. A simple
preparation such as this usually results in a multi-layered liposome consisting of concentric bilayers
resembling an onion in cross section. Special laboratory techniques (such as extrusion or sonica-
tion) can transform the multilamellar liposomes to unilamellar vesicles. All of these lipid bilayer
systems have had applicability as models for biological membranes for a variety of measurements
of membrane properties.
The lipid headgroups are generally polar and contain a variety of chemical structures. Choline,
ethanolamine, serine, glycerol, glucose, and inositol are just some of the chemical structures found
in the polar headgroups of lipids in membranes. Some of these carry charges and all can participate
in the hydrogen bonding structure of water. These structures are in turn covalently bonded to link-
ing molecules such as glycerol that in turn are covalently bonded to the hydrocarbon chains. In the
case of glycerol, the hydrocarbon chains are long fatty acids that are esterified to the glycerol. The
fatty acids contain from 12 to over 30 carbon atoms in a (usually) linear chain. The carbon–carbon
bonds can be single or double bonds. Generally the double bonds are cis (chemical synthesis can
produce trans double bonds) and generally they are not conjugated, enhancing their chemical stabil-
ity. If there is a single double bond in the fatty acid, it usually is located in the middle of the chain
in biological lipids. In some membrane lipids from bacteria, branch points occur in the hydrocarbon
chain containing single methyl groups.
As a specific example, one common lipid class of biological membranes is the phospholipids.
The headgroups of phospholipids are esterified to glycerol (at position 3′) and in turn the glycerol
is esterified to two fatty acids on positions 1′ and 2′ of the glycerol. Generally, the fatty acid esteri-
fied to position 1′ is saturated and the fatty acid esterified to position 2′ is unsaturated in biological
membranes, though exceptions to that pattern are not uncommon. The headgroups give identity to
the phospholipids. Thus if the headgroup is choline, the phospholipid is called phosphatidylcholine,
and if the headgroup is ethanolamine, the phospholipid is called phosphatidylethanolamine. For a
unique molecule of phosphatidylcholine, the hydrocarbon chains must be specified. Thus a phos-
pholipid with palmitic acid on position 1′ and oleic acid on position 2′ is called palmitoyl oleoyl
phosphatidylcholine or in shorthand, 16:0, 18:1 phosphatidylcholine, where the first number refers
to the length of the fatty acid (in carbons) and the second refers to the number of double bonds in
the fatty acid (Vance et al., 2008).
Introduction to Lipid Bilayers 3

LIPID BILAYER PROPERTIES

The structure of the lipid bilayer imparts to biological membranes some unique properties that are
vital to biological membrane function. Among these unique properties are relative impermeability
to water-soluble molecules, anisotropic internal dynamics, accessibility to multiple phase struc-
tures, and lateral diffusion restricted to two dimensions.
The hydrophobic effect drives the hydrocarbon chains from the amphipathic lipids into the
interior of the lipid bilayer, creating an energetically unfavorable environment for polar mol-
ecules. Therefore, for example, a molecule like choline with its net positive charge will partition
almost exclusively into the aqueous phase in a liposomal preparation. A molecule like coenzyme
Q with its long isoprenoid chain will partition very strongly into the membrane, with the chain
in the hydrophobic interior of the bilayer. In contrast, ethanol has solubility in both the aqueous
phase and the hydrophobic interior of the bilayer. Finally an amphipathic local anesthetic like
tetracaine is strongly oriented in a bilayer through the interaction of the positively charged por-
tion of the anesthetic with the aqueous phase and the hydrophobic portion with the hydrophobic
interior of the bilayer. The hydrophobic portion of the molecule aligns with the hydrocarbon
chains of the lipids.
This differential solubility is in part responsible for the ability of membranes to separate the inte-
rior from the exterior of a cell or a virus or to create independent compartments within a cell. The
impermeability of the lipid bilayer to polar solutes allows a differential in composition between the
outside of the cell and the inside of the cell, or between the cytoplasm and the lumen of an organ-
elle. The lipid bilayer essentially seals the compartment from diffusion of polar solutes between the
inside and the outside of the compartment. That property of the membrane restricts transport of
solutes largely to the protein components of the membrane that can exert specialized control on the
structure of the solute to be transported and the gradient across the membrane of that solute.
The structure of the lipid bilayer and the chemical structure of the lipids themselves effect an
anisotropy in the internal dynamics in the bilayer. The bilayer structure that the lipids spontane-
ously form in aqueous environments orients the long axis of the lipid molecules along a director per-
pendicular to the bilayer surface. (For a lipid like phosphatidylcholine, the phospholipid headgroup
orients perpendicular to the director or parallel to the bilayer surface with the positively charged
quaternary amine interacting with the negatively charged phosphate of a neighboring lipid.)
While the overall structure of the bilayer is stable, the internal components exhibit complex
dynamics. The molecule as a whole undergoes rotational diffusion about the director. The orienta-
tion of the director itself is time-dependent, often called wobble. The headgroup of phosphatidyl-
choline undergoes rotational diffusion at a different rate than the molecule as a whole and interacts
with an ensemble of partners.
The hydrocarbon chains exhibit internal dynamics. Rotations about carbon-carbon single bonds
occur readily, even more readily if the single bond is adjacent to a carbon–carbon double bond.
These bond rotations produce a series of conformational isomers according to the rules of chem-
istry of polymers. The arrangement about the carbon–carbon single bond can be trans or it can be
one of two gauche conformations. When the conformation of all the carbon–carbon single bonds is
trans, the chain is straight with no bends. When the conformation about one carbon–carbon single
bond is gauche, the hydrocarbon chain makes a bend about that bond. The following paragraph is
paraphrased from Yeagle (1993) and Seelig and Seeling (1974).
Order parameters offer an elegant means to describe the conformational behavior of lipid hydro-
carbon chains in lipid bilayers. The segmental order parameter for a segment of the hydrocarbon
chain of a lipid in this formalism can be represented by:

1
S= (3 < cos2θ > −1)
2
4 The Structure of Biological Membranes

where θ describes the angle with the director adopted by a particular

segment at a time t, and the segmental order parameter derives from a
time average of θ.
The order parameter is a quantitative statement about the confor-
mation of the segments of a lipid hydrocarbon chain. A straight chain
configuration (all-trans configurations about all the carbon–carbon
single bonds) is the state of highest overall motional order. As the inci-
dence of trans configurations decreases, the motional order of the chain
decreases. Because of the steric hindrance of the neighboring lipid mol-
ecules, one gauche conformer is coupled with another to create a kink
(Figure 1.3) in the chain (a single gauche conformer will cause a chain
to bend and invade the space occupied by the neighboring lipid and a
second coupled gauche conformer will reinstate the overall direction FIGURE 1.3 A kink in a
of the chain, perpendicular to the membrane surface). As the number lipid hydrocarbon chain.
of kinks in a chain increase, the molecular motional order parameter of
the chain decreases.
With these concepts in hand, other properties of the lipid bilayer can be readily described. Lipid
bilayers can exist in a gel state. In this state, the motional order is very high and all the hydrocarbon
chains are in the all-trans configuration. In this semi-solid state, lateral diffusion is dramatically
diminished. Pure lipids in this state feel to the touch like solid wax, though on a molecular basis
the lipid structures are quite different from wax. As the temperature of the preparation is increased,
a temperature is reached at which the lipid preparation undergoes a phase transition to the liquid
crystal state. In the liquid crystal state, motional order is much lower than in the gel state, lateral
diffusion of lipids is much more rapid, and the incidence of kinks in the hydrocarbon chains is much
higher than in the gel state.
The liquid crystal state is the predominant state of lipids in biological membranes. This makes
biological sense because membrane components (including proteins) are able to undergo lateral dif-
fusion in the plane of the membrane and conformational changes within the membrane that would
be inhibited by the gel state.
The distribution of segmental order parameters in the lipid hydrocarbon chains is anisotro-
pic across the bilayer. In the center of the bilayer, near the termini of the hydrocarbon chains,
the bilayer is highly disordered. Motional order increases as the carbon number decreases. The
region near the lipid headgroup is highly ordered (Figure 1.4). Furthermore, that highly ordered
region extends from approximately carbon 1–carbon 10 in the chains at a fairly constant value.
Then for higher numbered carbons, the motional order decreases dramatically toward the ter-
minal methyl group. As a consequence some very hydrophobic molecules that penetrate the
bilayer will concentrate in the center of the bilayer where the environment is most like a fluid
hydrocarbon.
High levels of cholesterol in a membrane induce a highly ordered state of the lipids. Cholesterol
consists of four fused rings that are rigid (a hydrocarbon tail on one end and a polar hydroxyl on the
other end of the molecule complete the structure). When cholesterol is incorporated into a mem-
brane, the rigid fused ring system locates in the region of high motional order of the hydrocarbon
chains (approximately carbons 1–10). The motional order of the hydrocarbon chains then increases
in a dose-dependent manner with increasing cholesterol content.
One property of lipid bilayers that may be surprising is the permeability of water across the
bilayer. Water is of course not hydrophobic and should not partition significantly into the hydropho-
bic hydrocarbon interior of a lipid bilayer. So how does water transit a membrane?
The dynamics properties described earlier provide a means to understand what appears to be a
quandary. When lipid hydrocarbon chains form a kink, a transient void results between the kink
and the neighboring hydrocarbon chain(s). The void, while small, is large enough to accommodate
a water molecule. Therefore a water molecule can transit a lipid bilayer by diffusing from transient
Introduction to Lipid Bilayers 5

Motional order

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

FIGURE 1.4 Order profile across one half of a lipid bilayer, plotted as a function of carbon number within
a lipid hydrocarbon chain.

void to transient void. In the absence of the kinks, there will be no transient voids and water mole-
cules should not be able to transit a membrane. A lipid bilayer in a gel state has few kinks in the lipid
hydrocarbon chains, so should not be permeable to water, and in fact is not. Cholesterol in a lipid
bilayer increases motional order, decreasing the incidence of these voids and decreasing the perme-
ability of the bilayer to small molecules. Molecules such as glycerol, which are larger than water,
also permeate lipid bilayers but to a much lesser extent than water molecules which are smaller.
Molecules like glucose which are much larger than glycerol exhibit minimal diffusion through lipid
bilayers. Therefore, what was noted earlier is correct; lipid bilayers are essentially impermeable to
virtually all polar solutes. Therefore lipid bilayers in biological membranes seal the membranes
against leakage of almost all polar molecules.
The role of kinks in lipid bilayers is not limited to transport of very small molecules. Considerable
evidence supports a role of these transient voids in the function of membrane proteins. Protein func-
tion usually involves conformational changes which require changes in the shape or net volume
occupied by the protein in the membrane. Transient voids, resulting from the kinks, can be recruited
to the lipid-protein interface to facilitate these shape changes of the protein necessary for function.
Thus most membrane proteins have no function in bilayers that are in the gel state. They also would
be expected to express diminished function in membrane subdomains known as rafts for the same
reason since rafts are postulated to have high levels of cholesterol (Simons et al., 2000).
Fluidity is a concept that arose in the 1970s as an attempt to describe the character of the inte-
rior of the lipid bilayer. While the meaning of this word in English might appear at first view to be
adequately characterizing the liquid crystalline phase of the bilayer, it does not. Fluidity is defined
as the inverse of viscosity and viscosity is defined in a three dimensional isotropic medium. Lipid
bilayers, as we have seen, are highly anisotropic and largely two dimensional, so the concept of
fluidity cannot be used to describe lipid bilayers (see Yeagle, 1993, for a more complete discussion).
The surface of lipid bilayers is determined by the structure of the lipid headgroups. These head-
groups are polar, sometimes with charges as part of their structure. They can hydrogen bond with
water and thus can accommodate their interface with the aqueous medium. They can also hydrogen
bond with each other in the surface of the membrane. A lipid like phosphatdylethanolamine with
its charged amino group can exchange hydrogen bonds with water. However because of the positive
charge on the amino group, there is a strong electrostatic attraction to the phosphate of the neighbor-
ing phosphatidylethanolamine and hydrogen bonds can form as well. Experiments show that the latter
interaction dominates. The effect is to blunt the polarity of the surface of a phosphatidylethanolamine
6 The Structure of Biological Membranes

bilayer. That surface is in fact hydrophobic relative to the surface of a phosphatidylcholine bilayer
where headgroups interact with neighboring phospholipids but not nearly as strongly due to the dis-
persed distribution of the positive charge on all the methyls of the quaternary amine and the poor
hydrogen bonding capability of a methyl group. Consequently, the (relatively) hydrophobic surface
of a phosphatylethanolamine bilayer readily aggregates with other phosphatidylethanolamine bilayer
surfaces in the same preparation. Interestingly this aggregation can be defeated by the same agents
(guanidine HCl and urea at high concentrations) that promote denaturation of water soluble proteins.
Phospholipid flipflop refers to the transmembrane movements of lipids. Under most circum-
stances in lipid bilayers, no significant movement of lipids occurs from one side of the bilayer to
the other on reasonable time frames. This is because it would require the transit of the hydrophobic
interior of the bilayer by the very polar lipid headgroup. However, a different situation occurs in
biological membranes where certain transmembrane proteins can facilitate such transmembrane
lipid movement.
Transmembrane lipid distribution is not always symmetric in pure lipid bilayers. In highly
curved lipid bilayers, such as sonicated phospholipid vesicles made out of more than one phospho-
lipid species, the phospholipid composition of the outer leaflet of the bilayer is not identical to the
composition of the inner leaflet of the bilayer. In biological membranes, the distribution of lipid
components is often asymmetric, maintained by enzymes that translocate specific phospholipids
across the bilayer.
Lipids can form structures other than lipid bilayers, depending upon the chemical properties of
the lipid. One extensively investigated non-bilayer structure is the HII phase, or hexagonal phase.
Lipids such as phosphatidylethanolamine can form tubes in which the headgroups, and the water,
are on the inside of the tube. The outside of the tube (hydrophobic) is in contact with other tubes
such that the structure looks like stacks of pipes. Although these structures are not found in biologi-
cal membranes, the propensity of lipids to form such structures can lead to instability in the lipid
bilayer in which such lipids are incorporated.

REFERENCES
Seelig, A. and Seelig, J. (1974) The dynamic structure of fatty acyl chains in a phospholipid bilayer measured
by deuterium magnetic resonance. Biochemistry 13: 4839–4845.
Simons, K. and Toomre, D. (2000) Lipid rafts and signal transduction. Nature Rev. Molecular Cell Bio 1:
31–40.
Vance, D. E. and Vance, J. E. (2008) Biochemistry of Lipids, Lipoproteins and Membranes (5th edn.),
Amsterdam, the Netherlands: Elsevier.
Yeagle, P. L. (1993) The Membranes of Cells, San Diego, CA: Academic Press.
 2 Membrane Proteins
Philip L. Yeagle

CONTENTS
Fundamentals of Structure.................................................................................................................. 7
References......................................................................................................................................... 11

All biological membranes contain a phospholipid bilayer, the fundamental architecture upon which
all membrane functions depend. As described in Chapter 1, lipid bilayers limit permeability and
permit the differentiation in composition between the inside of a cell or organelle and the outside.
Lipid bilayers thus must have played a critical role in the initial development of the earliest forms
of life.
Lipid bilayers offer an extended and readily extendable structure, stabilized by non-covalent
forces. Lipids are not gene products, but the lipid bilayer is easily replicated because it forms
spontaneously based on the chemistry of the lipid components (see Chapter 1). Lipid bilayers
establish a nearly two-dimensional world in a liquid crystalline matrix in which the membrane
components, including membrane proteins, undergo lateral diffusion in the plane of the mem-
brane. Because of the hydrophobic effect, very little translation of lipids or proteins in the third
dimension occurs.
Most specific functions exhibited by biological membranes are generated by membrane proteins.
Membrane proteins provide specific communication between the two compartments separated by
the membrane. While the lipid bilayer prevents non-specific communication by limiting perme-
ability, membrane proteins provide structurally specific pathways by which particular molecules
can diffuse from one side to another or in some cases can be actively transported from one side to
another against a concentration gradient.
Membrane proteins provide enzymatic functions essential to support transport across a mem-
brane as well as to support fundamental cellular metabolism. Membrane proteins permit trans-
membrane communication without transport of molecules across the membrane, providing certain
kinds of intelligent connections, for example, between the interior of a cell and its environment.
Chemical reactions at the heart of intermediary metabolism are enabled across or on mitochondrial
or chloroplast membranes by membrane proteins. Physical tethering between cells is supported by
cell membranes.
Although only a sketch, the preceding paragraphs reveal a complexity and an essentiality that
membrane proteins bring to biology, specifically through their properties as membrane proteins.
Because membrane proteins operate within or on a lipid bilayer, all membrane proteins exhibit
some general features.

FUNDAMENTALS OF STRUCTURE
Membrane proteins can be classified as integral or peripheral membrane proteins. Integral mem-
brane proteins have at least some of their mass buried in the hydrophobic interior of the membrane.
Integral membrane proteins can be either transmembrane proteins, extending from one side of the
lipid bilayer to the other such as a transport protein like lactose permease, or they may be anchored

7
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