membrane structure

Each membrane has two dense outer layers consisting of the polar phosphate heads, and an inner more fluid layer of the non-polar hydrophobic fatty acid tails.

The phospholipid is free to latterly diffuse across the membrane and the head can rotate on an axis. It is rare that the phospholipids will flip between each layer as this is thermodynamically unfavourable. The phospholipids are essentially in a liquid state. 

Hydrophobic molecules can freely diffuse through the membrane, whereas it is impermeable to ions and hydrophilic molecules.

There are 8 key lipid components: phospholipids (and sphingolipids), glycolipids and cholesterol. Phospholipids are separated into 5 groups depending on the small charged molecule that is attached to the phosphate head: phosphatidylethanolamine (PE), phosphatidylcholine (PC), phosphatidylserine (PS) and phosphatidylinositol (PI). They all have a glycerol backbone and 2 fatty acid tails.
 

The sphingolipid differs as they have a sphingosine backbone instead of glycerol. Sphingomyelin (SM) has choline as its small molecule, sphingosine backbone/tail and the other tail is a fatty acid.
 

The glycolipid galactocerebroside only differs from the sphingomyelin as it has a monosaccharide galactose as the small molecule instead of choline. Gangliosides have more complex oligosaccharides as the molecule attached to the phosphate head.
 

Cholesterol has a polar OH head, steroid rings and a hydrocarbon tail. This is why all steroid hormones are derived from cholesterol.

Membrane fluidity is determined by multiple factors. The fatty acid chains can be either saturated or unsaturated, where double bonding is always cis. Double bonds increase the fluidity as the kinks stop the lipids from packing so closely together. Longer carbon chains make the membrane less fluid. Cholesterol increases rigidity of the membrane, decreases fluidity and decreases permeability. It also has an anti-freeze property which stop it becoming a gel. The cholesterol can flip easily between the membranes as their heads are not as polar.

More complex cells have a higher composition of glycolipids as they are involved in cell recognition, cell adhesion, signalling and have electrical properties. For example, myelinated neurons have a high percentage of glycolipids compared to a red blood cell.

Phosphatidylinositol has signalling properties but the other membrane lipids contribute to structure.

Cholesterol increases stability and decreases permeability.

There are 50 lipid molecules to 1 membrane protein, however proteins take up 30-45% of the mass as they are large macromolecules.

There is a asymmetric distribution of phospholipids. The outer leaflet is made up of PC, SM and glycolipids which is involved in cell contact. The inner leaflet is made up of PE, PI and PS which is involved in signalling. The asymmetry is regulated by lipid flippase and floppase. Flippases move lipids from the outer leaflet to the inner leaflet, for example the P4-type-ATPase moves PS and PE. Floppases move lipids from the inner leaflet to the outer leaflet, for example the ABC ATPase transporter superfamily. These lipids are generated randomly in the ER so they asymmetry is achieved by the action of flippases and floppases.

Dying neurons are removed by microglia engulfing apoptotic cells. Neurons show they are dying by presenting PS on the outer leaflet, to ensure they are phagocytosed. The inhibition of flippases activates Ca2+ dependent phospholipid scramblases which increases PS in the outer leaflet. This is a key step at the end of apoptosis. It can be caused by:  oxidative stress, platelet plug formation in clotting, cells infected by a virus, sickle cell disease.

Proteins play 3 key roles in the membrane: structure, biochemistry and membrane signalling. They become associated with the membrane DURING protein synthesis or as a result of post-translational modifications.

Integral proteins are inside the membrane, with either transmembrane domains or they are anchored via an oligosaccharide. Peripheral proteins are non-covalently bonded to integral proteins.

Integral proteins are incorporated into the membrane of the ER during protein synthesis. The polar amino acids are found on the intracellular and extracellular sides of the membrane. The non-polar amino acids are found in the transmembrane domains. Proteins needed in the ER membrane have an ER signal sequence that binds to the SRP receptor on the ER membrane, which directs the protein through the translocon. Multipass proteins can be generated if N-terminus or C-terminus insertion is possible.

Post translational modifications happen in the cytosol. N-acylation is the attachment of a hydrocarbon chain to the N-terminus. N-myristylation anchors proteins to the cytosolic leaflet of the membrane with a 14C fatty acid myristoyl chain. This occurs when an N-terminal methionine residue is next to a glycine residue. The methionine is lost and the glycine becomes the N-terminal with a fatty acid tail. Examples of proteins with this modification include a-subunits of G proteins, catalytic subunit of PKA, and PP2B.

S-acylation is the attachment of a hydrocarbon chain to an S in the side chain of a cysteine residue at the proteins surface. S-palmitoylation anchors certain cytosolic proteins to the cytosolic leaflet of the membrane with a 16C fatty acid palmitoyl group at any point along the polypeptide chain. Examples of proteins with this modification include glutamic acid decarboxylase (GABA synthesis from L-glutamate), and t-SNAREs and SNAP25.

S-isoprenylation anchors proteins to the cytosolic side of membranes. A hydrocarbon chain containing isoprenyl group repeats are attached to a cysteine at the C-terminal. This is found on GTPases Ras and Rab.

These modifications still allow the proteins to undergo conformational change and to bind reversibly to the cytosolic leaflet.

Proteins are anchored extracellularly by adding a glycolipid glycosylphosphatidylinositol (GPI) to the C-terminal via a peptide-like linkage. Phospholipases may release these proteins as part of a signal pathway. Extracellular proteins include acetylcholinesterase, neural cel adhesion molecule and ephrin-A ligands.

Proteins can spin on their z axis, change conformation and move laterally. The interaction of proteins in the membrane are facilitated in 2 dimensions.

Lateral movement is restricted. This can be to cause aggregation of proteins within the cell membrane (lipid rafts), to tether macromolecules outside the cell (as part of the extracellular matrix), inside the cell (as part of the cytoskeleton) or to interact with proteins on  adjacent cells.

Lateral segregation forms rafts, which are more organised microdomains, where the membrane is compartmentalised into different processes at different locations. In the lipid rafts, there is more cholesterol, SM, saturated fatty acids and less PC, all to increase rigidity. They are also associated with the proteins CAVEOLIN which forms CAVELAE which are little pits in the membrane. Lipid rafts are needed to: facilitate protein trafficking to the membrane, regulate endo and exocytosis, in disease pathology, signalling complexes and metabolic localisation.