Chapter 1- Biomembranes

CCR5 and the HIV-resistant man

  • Mucus in endocervix entraps X4-tropic HIV

  • Epithelial cells express CCR5 and can become infected by transcytosis

  • Dendritic and Langerhans cells may become infected by R5 HIV

  • HIV can pass mucosal epithelial barriers through traumatic or disease-induced ulcerations

  • R5 HIV preferentially infects macrophages

  • DCs can trap viruses via DC-SIGN and carry them to regional lymph nodes

CELL MEMBRANES ARE DYNAMIC, FLUID STRUCTURES MADE OF LIPID AND PROTEIN MOLECULES

Fluid Mosaic Model (Singer and Nicholson)- All biological membranes are a very thin film of lipid and protein molecules, held together mainly by noncovalent interaction

Lipid Bilayer

  • relatively impermeable barrier
  • basic fluid structure

PHOSPHOGLYCERIDES, SPHINGOLIPIDS, AND STEROLS ARE THE MAJOR LIPIDS IN CELL MEMBRANES

  • amphiphilic = amphipathic
  • hydrophilic vs hydrophobic – self-assembly (spontaneous bilayer formation in aqueous environment)
  • self-sealing property
  • phospholipids – most abundant membrane lipid
  • nonpolar hydrocarbon tail
  • saturated vs unsaturated
  • kinks (cis double bond)
  • polar phosphate-based head
  • phosphoglyceride (glycerol)
  • sphingomyelin (sphingosine)

Omega-3 fatty acids

(highly unsaturated fatty acids found at high concentration in fish oil) showed beneficial effects. Incorporated primarily into PE and PC molecules of certain membranes, most notably in the brain and retina

Sphingolipids

  • built from sphingosine, a long acyl chain with an amino group (NH2) and two hydroxyl groups (OH) at one end
  • glycolipids have a sugar head group

Sterol

  • rigid ring structure

  • single polar OH group

  • short nonpolar hydrocarbon tail

  • intercalate between phospholipid molecules to be incorporated into biomembranes

THE LIPID BILAYER IS A TWO-DIMENSIONAL FLUID STRUCTURE

Membrane Fluidity

  • movement of lipid molecules
  • rotation
  • lateral diffusion
  • flip-flop

implication on the formation of lipid bilayer

  • phospholipid translocators

Fluidity is influenced by

  • composition
  • temperature

Phase transition

  • shorter chain length
  • more unsaturated
  • in conformers

Cholesterol has an unusual role in membranes

  • fills gaps between phospholipids to reduce the permeability to low molecular-weight solutes

  • disrupts the interactions between fatty acids, enhancing membrane fluidity

  • Cellular membranes are heterogeneous in composition.

Lipid rafts

  • accumulate cholesterol and glycolipids enriched concentration of some transmembrane proteins

THE ASYMMETRY OF THE LIPID BILAYER IS FUNCTIONALLY IMPORTANT

  • The lipid compositions of the two monolayers of the lipid bilayer in many membranes are strikingly different.
  • Case in point: human red blood cell (PC and SM in the outer monolayer) (PE and PS in the inner monolayer)
  • Lipid asymmetry is important in converting extracellular signals into intracellular ones
  • Protein kinase C binds to PS-rich region of the cytosolic monolayer as it requires negatively charged PS for activity
  • Phosphatidylinositol is modified by PI 3-kinase to serve as a protein- binding site

PROTEINS INTERACT WITH THE LIPID BILAYER IN DIFFERENT WAYS

integral membrane (transmembrane) proteins

  • function on both sides of the bilayer, e.g., transport proteins

lipid-linked membrane proteins

  • exclusively associated with one side of the bilayer only; e.g., signaling proteins

peripheral membrane (membraneassociated) proteins

  • attach to membranes transiently; e.g., Rab GTPases

  • Lipid anchors control the membrane localization of some signaling proteins

  • Src family of cytosolic protein tyrosine kinases

  • Ras family small GTPases

MANY MEMBRANE PROTEINS ARE GLYCOSYLATED

  • sugar component added in the lumen of ER and the Golgi body (glycoproteins) → noncytosolic layer

  • disulfide bonds only in the noncytosolic layer (help stabilize either the folded structure of the polypeptide chain or its association with other polypeptide chains)

  • cell coat or glycocalyx

MEMBRANE PROTEINS CAN BE SOLUBILIZED AND PURIFIED IN DETERGENT

  • detergents disrupt hydrophobic associations and destroy the lipid bilayer
  • small amphiphilic molecules
  • sodium dodecyl sulfate (SDS)
  • anionic – Triton X-100 --- nonionic
  • hydrophilic vs hydrophobic ends
  • micelle formation upon reaching CMC