Lecture 2
Fluid Mosaic Model
- A: Davson-Danielli-Robertson Model; B: Benson Model; C: Early protein-lipid mosaic model
- Protein:Lipid Ratio
- varies
- eg. 1 for red blood cell membranes
- eg. 3 for mitochondrial membranes
- e.g. 0.23 for myelinated portion of neurons
Integral protein types
- Monotopic – separate hydrophobic and hydrophilic domains (e.g. protein with membrane
spanning alpha-helix)
- First monotopic integral protein isolated and sequenced was glycophorin A from the
membrane of human red blood cells (now predict sequence directly from cDNA
sequences).
- 131 a.a sequence could be subdivided into:
- 72 a.a N-term sequence containing charged residues and all of the
saccharide units (ectodomain)
- 23 a.a stretch composed mainly of hydrophobic residues
- 36 a.a C-term sequence containing charged residues (endodomain)
- Signaling across these proteins requires the formation of dimers to activate the interior
domain. A conformational change alone is not energetically favourable. (e.g. Tyrosine
kinases...later)
- Polytopic proteins – several hydrophobic and hydrophilic domains weaved into the membrane
- number of transmembrane domains and the side on which C and N terms are
located can differ from protein to protein
- Signaling across these proteins involves a conformational change (e.g . Gprotein coupled receptors....later)
- Transport proteins – for transport of small ions and hydrophilic substances across membrane
which is impossible by simple diffusion
- consist of a complex of transmembrane protein subunits that create a
transmembrane water filled channel
- number of subunits and the side on which C and N terms are located can differ
from channel to channel (subunits can be identical or somewhat different)
- Transport across these proteins involves a conformational change which
opens channel and allows molecules across the plasma membrane after ligand
binding (e.g .Nicotinic acetylcholine receptors composed of 5 subunits)
Asymmetry of the Membrane
Lipids:
- lipids with highly polar head groups show asymmetric distribution
- asymmetry of lipids results in a net negative charge on the cytoplasmic side of the
bilayer
- How is this asymmetry maintained? By themselves, many lipids move from one layer to the
other through transbilayer diffusion in order to reach an equilibrium.
- Flippases and floppases are ATP dependent proteins that maintain the asymmetry of
lipids at the plasma membrane of all eukaryotes studied to date. Scramblases also
mediate the movement of lipids from one leaflet to the other, but their activity appears
to be ATP independent. These controlled lipid movements play a major role in the ability
for the membrane to bend (i.e. to form a vesicle).
Example: When intracellular calcium levels increase, scramblase moves PS from the
inner to the outer layer. This signals also signals that the cell is undergoing controlled
cell death, or apoptosis. PS exposure is necessary for platelet aggregation because it is a
cofactor for the conversion of prothrombin to thrombin.
Membrane Fluidity
- many proteins are free to diffuse individually or in groups throughout the plane of the
membrane
- however, some are fixed in place because they are anchored to peripheral proteins on the
other side (e.g. spectrin restricts lateral diffusion of proteins)
Membrane Domains...so not fully fluid
- Caveolae
- dense flask shaped invaginations in the plasma membrane
- contain high levels of the protein calveolin, a protein that binds cholesterol
- important for cholesterol uptake, endocytosis, signal transduction and maintaining
vesicle integrity
- disrupting cholesterol disrupts calveolae
- knockout shows decreased vesicle integrity
- another knockout shows increased cell death due to the hyperactivation of
certain signaling pathways
- Lipid rafts
- high cholesterol contents
- have high levels of fully saturated lipids, such as sphingolipids
- may also contain proteins anchored by glycolipids
- Protein domains formed by anchoring of actin cytoskeleton, spectrin (anchored by ankyrin) and
other intracellular proteins.
- This model has been referred to as the membrane-skeleton-fence
- supported by disruption of actin cytoskeleton by removal of cytoplasmic domains
- Certain phospholipids also appear to be concentrated to certain domains. Anchored-protein
picket model suggests that proteins linked to the cytoplasmic actin meshwork create a fence
that confines the movement of certain phospholipids
Lastly...
- Though the cell membrane offers the cell protection from the environment, there is nothing to
protect it from the environment. It therefore needs to be resilient.
- However, there are many substances that are able to selectively disrupt plasma membrane
components. This may result in small scale changes, or a complete destruction of the membrane
- Example: mobile phone use and close range electromagnetic fields? Some studies suggest that
membrane permeability of neurons may be affected
References
1. Singer (2004). Some early history of membrane molecular biology. Annual Reviews in Physiology, 66.
1-27.