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Summary Molecular Cell Biology
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This summary is made using the slides, notes taken in class and the book Molecular Cell biology (Lodish). It contains all the needed information for the examen
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Samenvatting DEEL 1 Moleculaire Celbiologie
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Summary - Molecular therapy (NWI-BM078) 2023/2024
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Samenvatting Cel I Fysische en chemische grondslagen: partim Algemene Chemie
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Voorbeeld van de inhoud
Laura van den EndBiomembrane structure
- Depends on the length of FA chains, if double
In general bonds and on the T (FA chains aggregate and
Role: many aspects of cell structure and function exclude water molecules from the core)
- Plasma membrane defines the cell and separates - Use enzymes to remove chains → more
the inside from the outside micelles
- Define intracellular organelles (nucleus mitochon- - PL of the composition present in cells
drion and lysosome) spontaneously from symmetric PL bilayers (each
- Structural role, but not rigid structures layer = leaflet)
- Bend and flex in three dimensions while - FA chain minimize contact with water by
maintaining their integrity. Due to the aligning themselves tightly together in the
abundant non-covalent interactions that hold center of the layer ⇒ 3-4 mm thick
lipids and proteins together hydrophobic core
- Within the plane of the membrane mobility of - Very stable bc of the interactions (H-bond + VDW)
lipids and proteins ~ fluid mosaic model: “the
lipid bilayer behaves in some respects like a two- PL bilayers form sealed compartment
dimensional fluid, with individual lipid molecules - Generating synthetic PL bilayers in lab using
able to move past one another as “well as spin in chemically pure PL and lipid mixtures of
place”. composition found in cell membranes
⇒ typical shapes of organelles - 3 important properties
⇒ dynamic processes of membrane budding
and fusion 1. Impermeable to water-soluble solutes
2. Stability: hydrophobic and VDW interactions btw
Same basic architecture = a phospholipid bilayer in FA chains maintain the integrity of the interior
which proteins are embedded 3. Spontaneous formation of sealed closed
- Hydrophobic area restricts movement of water- compartments, separating the aqueous space on
soluble substances from one side to the other = the inside from that on the outside
permeability barrier - Edge is exposed to aqueous exterior =
- Maintain characteristic differences between unstable → in aqueous solution: spontaneous
inside and outside of the cell/organelle sealing of the edges, forming a spherical
- Embedded proteins endow the membrane bilayer that encloses an aqueous central
with specific functions compartment = liposome.
- Move laterally and spin within plane of the - Important implications for cellular membr-
membrane anes: no membrane in a cell can have an edge
- Non-covalent interactions between PL and with exposed hydrocarbon FA chains ⇒ al
between PL and proteins membranes form closed compartments
- Each cellular membrane: own set of proteins
(integral, lipid-anchored, peripheral) → multitude - Internal face = cytoplasmic = oriented toward the
of different functions. interior of the cell
- External face = exoplasmic = directed away from
Composition and structural organization the cytosol, presented towards the extracellular
Phosphoglycerides are the most common PL → the space or external environment = the outer limit of
key feature is that they are amphiphatic (hydro- the cell
phobic and hydrophilic groups) ⇒ similar for organelles and vesicles surrounded by
a single membrane → lumen = topologically
Pure phospholipid layers equivalent to extracellular space
- Do not exist in nature
- One of these structures (spherical micelles, - Nucleus, mitochondrion and chloroplasts are
enclosed by 2 membranes, separated by a small
liposomes, sheet-like phospholipid bilayers) will
inter membrane space → exoplasmic faces of the
automatically be formed when PL are put in water
inner and outer membrane border the inter
and mechanically mixed
membrane space between them → endosymbiont
hypothesis.
Molecular cell biology
, Laura van den End
Different cell types exhibit a variety of shapes, STEROLS
complementing a cell’s function - Basic structure: four-ring isoprenoid-based hydro-
- Smooth, flexible surface of erythrocyte pm → carbon
squeeze through narrow blood capillaries - Small differences in biosynthetic pathways and
- Long slender extension of pm (flagellum) → structures of fungal and animal sterols = basis of
allows fluid to flow across the surface of a sheet of most anti-fungal drugs currently in use
cells, or a sperm to swim toward an egg - Hydroxyl substituent on one ring → amphipathic
(lacks a phosphate-based head group → not PL)
3 principal classes of lipids - Too hydrophobic to form a bilayer structure on
their own
PHOSPHOGLYCERIDES - Intercalate between phospholipid molecules
- Derivatives of glycerol-3-phosphate - Influence on membrane fluidity
- 2 esterified FA chains and a polar head groups - Provide rigidity for mechanical support
esterified to the phosphate - Cholesterol = precursor for several important
- FA can vary in length and saturation bioactive molecules
- (-) phosphate group and (+) groups or OH groups - Bile acids: made in liver, help emulsify
on head group → strong interaction with water dietary fats for digestion & absorption
- At neutral pH: some PG: no net electric charge; - Steroid hormones produced by endocrine
others single net (-) charge ⇒ polar head groups cells (e.g., adrenal gland, ovary, testes)
pack together into the bilayer structure - Vitamin D produced in the skin and kidneys
- Phospholipases act on PG → lysophospholipids - Another critical function: covalent addition to
- Lack one of the two acyl chains (micel Hedgehog protein: a key signaling molecule
formation) in embryonic development
- Important signaling molecules, released from
cells and recognized by specific receptors Mobility
- Presence can affect the physical properties of - Thermal motion: permits lipid molecules to rotate
the membranes freely around their long axes and diffuse laterally
- Plasmalogens within each leaflet
- One FA chain attached to glycerol by an ester - A typical lipid molecule exchanges places in a
linkage; one attached by an ether linkage leaflet 107 times/sec and diffuses several µm/sec
- Similar head groups as other PG at 37ºC ⇒ bilayer is 100x more viscous than water
- Abundant in human brain and heart tissue - Lipids diffuse more slowly in bilayer than in
- Greater chemical stability (ether linkage) or aqueous solvent, the length of a typical bacterial
the subtle diff in their 3D structure may have cell (1µm) in 1 sec (the length of an animal cell in
(yet unrecognized) physiologic significance. 20 seconds)
- Artificial pure phospholipid membranes below
SPHINGOLIPIDS 37ºC: phase transition form liquid like state to gel
- Derived from sphingosine = amino alcohol with like state → PL with long saturated FA chains
long hydrocarbon chain assemble into highly ordered gel-like bilayer →
- Long-chain FA attached via amide bond to little overlap of the non polar tails in the leaflets
sphingosine amino group - Heat disorders the non polar tails →
- Some: phosphate-based polar head group transition form a gel to a fluid within T range
- E.g. sphingomyelin (SM) = most abundant of only a few degrees → chains disordered →
- Phosphocholine attached to sphingosine = a bilayer decreases in thickness
phospholipid (similar in shape to PG + can
form mixed bilayers with them) PURE MEMBRANE BILAYERS (W/O PROTEINS)
- Other: amphipathic glycolipids - PL and SL rotate and move laterally
- Polar head groups are sugars not linked via - No spontaneously migration from one leaflet to
phosphate group → technically not PL the other or flip-flopping
- E.g. glucosylcerebroside (GlcCer): 1 glucose - Energetic barrier is too high → would require
unit attached to sphingosine moving polar head group from aqueous
- Or: complex glycosphingolipids (gangliosides environment through hydrocarbon core ⇒
1 or 2 branched sugar chains (oligosac- special membrane proteins to flip proteins
charides) containing sialic acid groups
attached to sphingosine
Molecular cell biology
, Laura van den End
FRAP (FLUORESCENCE RECOVERY AFTER - Short FA chains: less surface area → fewer
PHOTOBLEACHING) VDW interactions ⇒ more fluid bilayers
- Quantify lateral movements of specific PM - Bending in cis-unsaturated FA chains → less
proteins and lipids stable VDW interactions → more fluid bilayer
- Monitor movement of PL containing fluorescent - Straight saturated chains: pack more tightly
substituent and proteins with a specific Ab tagged together
with fluorescent dye - Cholesterol is important in maintaining appro-
- Determine at which rate membrane molecules priate membrane fluidity
move = diffusion coefficient - Restricts random movement of PL head
groups at outer surfaces of leaflets → effect
(a) Experimental protocol on long PL tails depends on concentration
- Cells labeled with fluorescent reagent that binds - Normal [ ] → interaction of steroid ring with
uniformly to specific membrane lipid/protein long hydrophobic tails tends to immobilize
- Laser light is focused on small area → bleaching lipids → ↓fluidity → helps organize PM into
reagent → reducing fluorescence discrete subdomains of unique lipid and
- In time, fluorescence of the bleached patch protein composition
increases as unbleached fluorescent surface - Low [ ] → steroid ring separates and
molecules diffuse into it and bleached ones diffuse disperses PL tails → inner regions of
outward membrane become more fluid
- ⇒ extent of fluorescence recovery proportional to
fraction of labeled molecules mobile in membrane THICKNESS
- Influence on distribution of other membrane
(b) Results of FRAP experiment with human components, such as proteins
hepatoma cells treated with fluorescent antibody - Golgi: certain enzymes have short transmembrane
specific for asialoglycoprotein receptor protein segments = adaptation to lipid composition and
- 50 % of fluorescence returned to bleached area → contributes to retention of enzymes
50% of receptor molecules in illuminated - Sphingomyelin associates into more gel-like and
membrane patch were mobile and 50 % immobile. thicker bilayer than PG
- Bc rate of fluorescence recovery is proportional to - Cholesterol and other molecules that decrease
rate at which labeled molecules move into region, fluidity also increase thickness
the diffusion coefficient can be calculated
CURVATURE
Lipid composition - physical properties - Depends on relative sizes of the polar head groups
- Typical cell: many different types of membranes, and the non polar tails of constituent PL
each with unique properties derived from its - Long tail + large head group = cylindrical shape
particular mix of lipids and proteins → bilayer flat
- Variation in lipid composition contributed by - Small head group = cone shape → bilayer curved
several phenomena - May play a role in
- Formation of highly curved membranes, such
1. Relative abundances of PG and SL as sites of viral budding
- ER: PG synthesis; Golgi: SL synthesis - Formation of internal vesicles from PM
2. Movement of membranes from one cellular - Specialized stable membrane structures such
compartment to another can selectively enrich as microvilli
certain membranes in lipids such as cholesterol - Curvature can be caused by proteins binding to
3. Response to environment: different types of cells the surface of PL bilayers → important in
→ membranes with differing lipid composition formation of transport vesicles that bud from a
donor membrane
FLUIDITY
- Depends on lipid composition, structure of the PL Exoplasmic vs cytosolic lea ets
hydrophobic tails and the temperature - All biomembranes have an asymmetry in lipid
- VDW interactions and the hydrophobic effect → composition across the bilayer: most PL are
non polar tails aggregate present in both membrane leaflets, but some are
- Long, saturated FA chains: greatest tendency more abundant in one leaflet
to aggregate, packing tightly together in gel-
like state.
Molecular cell biology
fl
, Laura van den End
- e.g. PM of human erythrocytes and MDCK cells: Lipid droplets
- Exo: almost all the sphingomyelin and
phosphatidylcholine → less fluid CHARACTERISTICS
- Cyt: phosphatidyletanolamine, -serine, and - Vesicular structures, containing the ‘bad’ lipids
-inositol (net (-) charge) → more fluid - Composed of triglycerides and cholesterol esters
- (-) charge: stretch of aa on cytoplasmic face of a - Originate from the ER
single-pass membrane protein, in close proximity - Visualized with a lipophilic dye: Congo red
to transmembrane segment, often enriched in - Serve as platforms for storage of proteins targeted
positively charged residues = inside positive rule for degradation
- Segregation of lipids across the bilayer → - Formation increased by feeding cells oleic acid
influence membrane curvature → cholesterol
evenly distributed BIOSYNTHESIS
- Details and function unknown
- Experiment: susceptibility to hydrolysis by phos- - Delamination of ER membr →
pholipases → determine relative abundance PL insertion of triglycerides and
- Phospholipases cleave ester bond via which cholesterol esters
acyl chains and head groups are connected to - Lipid “lens” grows by inser-
the lipid → cannot cross the membrane → tion of more lipid, until a
only cleave off the head groups of lipids in droplet is hatched by scission
the exoplasmic face. from the ER → droplet is
- PLC is a cytosolic enzyme → site of synthesis enwrapped by PL monolayer
determines the topology
- PL donor spontaneously migrate, or flip-flop in
Membrane proteins: structure and
pure bilayers → asymmetry reflects where lipids
are synthesized function
- Sphingomyelin (SM): synthesized in luminal
golgi → exoplasmic face Interaction with membranes
- Phosphoglycerides: synthesized on cyt face of
ER → cyt face of PM INTEGRAL
- Does not account for preferential location of - 3 domains: cytosolic, exoplasmic, membrane
phosphatidylcholine in exo leaflet → flippase - Cyt + exo: hydrophilic exterior surface → interact
can flip the PGL from one leaflet to the other with aqueous env on cyt and exo faces
using ATP - Membrane spanning: hydrophobic aa whose side
chains protrude outward and interact with the
Cholesterol and SL cluster with hydrophobic hydrocarbon core of the bilayer +
consists of one or more α-helices or β-strands
proteins in micro domains
- Discovery: not all the molecules are soluble and
LIPID ANCHORED
remain after treatment → cholesterol and SM form - Bound covalently to one or more lipid molecules
lipid rafts - Hydrophobic tail of the lipid is embed-ded in one
- Microdomains contain a lot of cholesterol and SM
leaflet and anchors the protein to the membrane
- Can be disrupted by methyl-β-cyclodextrin - Polypeptide chain itself does not enter the bilayer
(extracts cholesterol out of membranes) or by
antibiotics; filipin (sequester cholesterol into
PERIPHERAL
aggregates within the membrane) - Do not contact hydrophobic core of bilayer
- ⇒ cholesterol is important to maintain - Bound to the membrane
integrity of rafts - Indirect: interact w integral/lipid-anchored
- Rafts enriched in glycolipids → microscopic - Direct by interactions with lipid head groups
visualization: label with cholera toxin (binds to - Bound to either cytosolic or exoplasmic face
specific gangliosides) - Cytosolic: association of cytoskeleton through
- Raft fractions contain subset of PM proteins →
peripheral (adapter) proteins → support for
sense extracellular signals → transmit into the
membranes → cell shape and properties
cytosol → facilitate cell-surface signaling. - Exoplasmic: attached to ECM components or
cell wall (bact/plant → crucial interface
between cell & its environment
Molecular cell biology
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