Biochemistry 4:
Cellular Biochemistry
Ulrike Gaul
Thomas Becker
Julia von Blume
Ralph Böttcher
Veit Hornung
Carsten Grashoff
Markus Moser
Boris Pfander
Teaching assistance:
Sara Batelli
Lecture 2
Membrane structure
Plasma membrane
A living cell is a self-reproducing system of molecules held inside a container. That
container is the plasma membrane – a fatty film so thin and transparent that it can’t be
seen directly in the light microscope, only after fixation and osmication in the TEM.
The membrane consists of a double layer of lipid molecules about 5 nm thick, and
various types of proteins.
Plasma membrane – properties and functions
The plasma membrane:
 serves as a barrier (retaining the cell’s content)
 mediates nutrient import/waste export – to achieve this exchange, the membrane is
penetrated by highly selective channels and pumps
 Some membrane proteins sense changes in the environment and transduce signals
to the inside of the cell ( signal transduction)
 when a cell grows or moves, so does the plasma membrane ( cell motility)
 when pierced, it doesn’t tear but rather quickly reseals
Internal membranes
Eukaryotic cells have many internal membranes that enclose different compartments
(ER, Golgi, lysosomes, peroxisomes).
These membranes are also composed of lipids and proteins. The plasma membrane
contains ~ 25% protein, internal membranes contain up to 75% protein.
Membrane lipids
Key feature of membrane lipids is that they are amphipathic, with a hydrophilic head
and one or two hydrophobic tails.
Membrane lipids
3 types of molecules: phospholipids, sterols, and glycolipids
Lipid bilayer
Hydrophilic molecules dissolve in water; hydrophobic molecules form droplets in
water
Amphipathic molecules form a bilayer – hydrophilic heads exposed to water,
hydrophobic tails face each other. The bilayer arrangement is energetically
favorable.
Lipid bilayer
The same forces also
 make the bilayer tear-resistant = self-sealing
 lead to the formation of sealed compartments
Lipid bilayer - resilience
Lipid bilayer as a two-dimensional fluid
The lipid bilayer is a two-dimensional fluid.
Phospholipids can rapidly flex, rotate (30,000 revolutions/min), and diffuse laterally
(2 µm/sec).
However, flip-flop between the two leaflets is very rare (1 molecule/month).
Lipid bilayer
The fluidity of a lipid bilayer depends on its composition and ambient temperature.
Particularly important are the hydrocarbon tails:
 the closer and more regular the packing of the tails, the more viscous and less
fluid the bilayer
 shorter tails  more fluid,
 more double bonds (=kinks)  more fluid
Another factor is the cholesterol content, which varies in animal cells:
 cholesterol is short and rigid  stiffens bilayer
Lipid bilayer
The lipid bilayer is asymmetrical:
The inner and outer leaflet contain different sets of phospholipids and glycolipids
 All glycolipids are in outer leaflet
 Cholesterol is equally distributed
 Phosphatidylserine/inositol are in inner leaflet
Membrane proteins are inserted with a specific orientation (more later)
Lipid bilayer - synthesis
Synthesis of lipid bilayer:
New phospholipids (PLs) are added to
luminal leaflet of ER
Flippases transfer lipids to other half
of bilayer  growth of membrane
Selective flippases enrich certain PLs
in outer leaflet
Lipid bilayer - synthesis
Asymmetric glycolipid distribution is generated differently:
ER/Golgi  vesicle  plasma membrane
Orientation of bilayer relative to cytosol stays the same
Glycolipids receive their sugar modifications on the inside of the Golgi –
when vesicle is transferred, this becomes the outer leaflet of the plasma membrane
Membrane proteins
Aside from its role as a permeability barrier, the lipid bilayer serves as a platform for
the activity of the membrane proteins.
50% of the plasma membrane mass is protein, but since the lipids are much smaller,
there are 50 times more lipid than protein molecules.
Membrane proteins serve a variety of functions:
 Transport of nutrients, metabolites and ions (next lecture)
 Anchoring the membrane to macromolecules on either side (ECM, cytoskeleton)
 Receptors for detecting chemical signals in environment and relaying them to the
cell’s interior
 Enzymes that fulfill signaling and other functions
Membrane proteins
Proteins can be associated with the bilayer in several ways:

By extending through the bilayer, with part of their mass on either side. Like the lipids,
transmembrane proteins have both hydrophobic and hydrophilic regions – the
hydrophobic regions lie within the bilayer, nestled against the hydrophobic tails of the lipid
molecules. The hydrophilic regions are exposed to the aqueous environment on either side
of the membrane.

Other proteins are located entirely located in the cytosol, associated with the inner leaflet
by an amphipathic -helix exposed on the surface of the protein.

Some proteins lie entirely outside the bilayer on either side, attached to the membrane only
by one or more covalently attached lipid groups.

Some proteins are bound indirectly through protein-protein interactions.
Membrane proteins
A polypeptide chain usually crosses the
bilayer as an -helix.
The membrane-spanning segments are
largely composed of amino acids with
hydrophobic side chains. These side chains
are exposed to the hydrophobic tails of the
lipids, the peptide bonds (polar/hydrophilic)
are inside – since there is no water in the
membrane, the protein maximizes hydrogen
bonds within the backbone, which is best
achieved in an  -helix.
Single membrane-spanning proteins are often
receptors for extracellular signals.
Proteins that function as transporters/pores
are usually more complicated.
Membrane proteins
Water channel with 5 membranespanning segments, all -helices:
hydrophobic residues are on the outer,
lipid-facing side
hydrophilic residues are on the inner,
pore-facing side of the channel
 -helices are the most common, but …
Membrane proteins
… some proteins cross the bilayer as a
ß-sheet that is curved into a cylinder:
side chains that face the inside of the
barrel are hydrophilic and line the
aqueous channel
hydrophobic side chains contact the
bilayer
ß-sheets are only good for wide
channels (limited bending).
One class are the porins that let
nutrients and ions pass, but not large
molecules (such as antibiotics and
toxins)
The complete structure is known for relatively few membrane proteins
most information about structure comes from X-ray crystallography. Due to the
hydrophobicity of the membrane proteins, they are harder to crystallize – hence less
has been done.
Membrane supported by cell cortex
The plasma membrane is reinforced by the cell cortex.
The membrane itself is extremely thin (5 nm) and fragile – it is typically supported by a
mesh of proteins attached to the membrane via transmembrane proteins.
The shape of a cell and the mechanical properties of its membrane are determined by
this cell cortex.
Example: red blood cells
Membrane supported by cell cortex
The red blood cell cortex is simple and well understood:
Main component is spectrin – long flexible rod of 100 nm length, connected to
membrane through intracellular attachment proteins.
Red blood cells have a specific shape and mostly need mechanical strength to
squeeze through blood vessels, while other cell types have more complicated
shapes they need to change – their cell cortex is much more complex.
Membrane supported by cell cortex
Cells have various means to restrict the movement of membrane proteins:
tethering to the cell cortex
tethering to extracellular
matrix molecules
by cell-cell contact
Cell junctions
diffusion barriers through tight junctions – apical vs. baso-lateral surfaces
Carbohydrate coating
The cell surface is coated with carbohydrates.
Not only outer-leaflet lipids have sugars attached (glycolipids), but also the
extracellular portions of membrane proteins (glycoproteins, proteoglycans).
This carbohydrate layer absorbs water, lubricating the surface of the cells.
Complicated cell-specific differences in sugar chains (also very speciesspecific)…. Distinctive “clothing” of cells.
Summary – essential concepts
 Cell membranes enable a cell to create barriers that confine particular molecules to
specific compartments.
 Cell membranes consist of a continuous double layer – a bilayer – of lipid molecules
in which proteins are embedded.
 The lipid bilayer provides the basic structure and barrier function of all cell
membranes.
 Membrane lipid molecules have both hydrophobic and hydrophilic regions. They
assemble spontaneously into bilayers when placed in water, forming closed
compartments that reseal if torn.
 There are three major classes of membrane lipid molecules: phospholipids, sterols,
and glycolipids.
 The lipid bilayer is fluid, and individual lipid molecules are able to diffuse within their
own monolayer; they do not flip from one monolayer to the other.
 The two layers of the plasma membrane have different lipid compositions, reflecting
the different functions of the two faces of a cell membrane.
 Some cells adjust their membrane fluidity by modifying the lipid composition of their
membranes.
Summary – essential concepts
 Membrane proteins are responsible for most of the functions of a membrane, such
as the transport of small water-soluble molecules across the lipid bilayer.
 Transmembrane proteins extend across the lipid bilayer, usually in one or more helices, but sometimes as a ß-sheet curved into the form of a barrel.
 Other membrane proteins do not extend across the lipid bilayer, but are attached by
non-covalent association with other membrane proteins or by covalent attachment
to lipids.
 Most cell membranes are supported by an attached framework of proteins, the cell
cortex.
 Although many membrane proteins can diffuse rapidly in the plane of the
membrane, cells have ways of confining proteins to specific membrane domains
and of immobilizing proteins by attaching them to extra- or intracellular
macromolecules.
 Many of the proteins and some of the lipids exposed on the surface of cells have
attached sugars, which lubricate and protect the cell surface and play a role in cellcell recognition.