2b Membrane Structure

Most span the entire lipid bilayer, making them amphipathic.
- Cytosolic and exoplasmic domains: Mainly polar (hydrophilic).
- Transmembrane domain: Predominantly nonpolar (hydrophobic).
Alpha helix needs at least 20 amino acids to cross the lipid bilayer.
- Not all amino acids need to be hydrophobic, but the majority should be.
Bound to the lipid bilayer through hydrophobic interactions.
- Difficult to dissociate from the membrane; requires detergents or solvents.
Stabilised by:
- Hydrophobic interactions with interior lipids.
- Ionic interactions with polar head groups of phospholipids.

3. 6 amino acids per turn.
Amides of hydrogen interact with carbonyl oxygen four residues further along the chain to form the alpha helix.
Hydrophobic amino acids commonly found:
- Glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan (nine total).
Polar uncharged amino acids found in extracellular domains:
- Serine, threonine, cysteine, tyrosine, asparagine, glutamine (six total).

Used to predict if a protein is a transmembrane protein.
Alpha helix needs to be ~20 amino acids long to span the lipid bilayer.
Baseline at zero:
- Negative values: Hydrophilic residues.
- Positive values: Hydrophobic residues.
If there are more than 20 amino acids in the positive range, it indicates a membrane-spanning section.
Example: Glycophorin
- Hydrophilic section, followed by hydrophobic, then hydrophilic.
- Suggests part of the protein is outside the cell, part within the membrane, and part within the cytoplasm.
Example: Bacteriorhodopsin
- Seven distinct hydrophobic domains.
- Suggests seven alpha helices clustered together.
Beta barrel structures:
- Cannot be predicted effectively, as they require less than 10 hydrophobic amino acids.
Prediction:
- Hydrophobicity analysis predicts that up to 30% of proteins encoded by the human genome could be transmembrane proteins.

Major protein in red blood cells (erythrocytes); half a million copies per cell.
Single-pass transmembrane protein (crosses the bilayer once).
23-residue hydrophobic alpha helix spanning the membrane.
Positively charged lysine and arginine amino acids (blue spheres) bind to negatively charged phospholipid groups on the cytosolic leaflet, anchoring the protein.
Extracellular domain is heavily glycosylated (attached to serine, threonine, and arginine during protein synthesis in the ER).
Homodimer: Two monomers participate in van der Waals interactions.
- Side chains of helices project towards hydrocarbon tails of phospholipids.
Hydropathy plot correlation:
- Large hydrophilic section (negative range) corresponds to the extracellular domain.
- Hydrophobic peak (positive peak) corresponds to the alpha helix spanning the membrane.
- Smaller hydrophilic domain (negative) corresponds to the cytosolic domain.

Major protein in erythrocyte plasma membrane
Single-pass transmembrane protein.
Sialoglycoprotein
MNS blood group antigen.
Forms dimers e.g. homodimer
Recognised by Plasmodium falciparum (malaria parasite), which allows it to enter red blood cells.

Structure reflects the hydrophobic plot with seven transmembrane domains.
Used by Archaea as a proton pump.
Contains retinal (a chromophore that absorbs light) covalently linked to lysine.
Activated by a single photon of light, causing a change in retinal shape and protein conformation.
Transfers photons from inside to outside the cell creating a photon gradient that drives energy-requiring processes.
In bright light, each molecule pumps several hundred protons per second.
Enables ATP production by another protein in the cell's plasma membrane.
Structure determined by protein crystallography, showing phospholipids interacting with the protein.

Present in the membrane of archaea (e.g., Halobacterium salinarium).
Multipass transmembrane protein (seven transmembrane helices).
Single polypeptide with hydrophobic and hydrophilic residues.
Functions as a proton pump:
- Transports protons from inside to outside the cell.
- Creates a proton gradient.
- Converts photons of light into chemical energy.

Similar structure to bacteriorhodopsin (single polypeptide chain with seven transmembrane helices).
Ligand binding causes conformational changes on the cytoplasmic domain.
Largest family of cell surface receptors.
Mediate responses from the external environment and convey signals internally.
GPCRs that bind protein ligands have large extracellular domains.
Example: Beta-2 adrenergic receptor (for adrenaline).
Interactions with the ligand change interactions between amino acids, aiding in conformational change.
Only parts of the alpha helix in contact with phospholipids need to be hydrophobic.

Third class of transmembrane proteins.
Open-ended barrel structure created by beta sheets folding.
Beta sheet composed of 8-20 beta strands.
Structure determined by X-ray crystallography.
Receptors or enzymes that have a beta barrel structure will not form a channel.
Porins: Beta barrel proteins that form a water-filled channel, allowing small hydrophilic molecules to cross the membrane.
- Found in the outer membrane of Gram-negative bacteria.
- Can be generic or selective.
  - Selective porins have a narrowed barrel to allow only specific molecules to pass (e.g., maltoporin for maltose oligomers in E. coli).
Residues facing the lipid bilayer are hydrophobic, while residues facing the interior of the barrel are hydrophilic (e.g., in porins).