Lipid Rafts

what do efficient cell signal transduction cascades require?

efficient protein-protein interactions (proteins are close together physically and can interact quickly)

describe the steps of a typical cell signal transduction cascade

1. ligand binds to receptor on cell surface

2. cellular proteins recruited to cytoplasmic tails on receptor and associate at/near inner leaflet of PM (membrane-associated proteins)

3. protein-protein interactions (e.g. phosphorylation) activate downstream proteins (cytoplasmic)

4. result of signal transduction cascade: activation of TF that either:

   1. turns on a gene (translation of protein)

   2. turns off a gene (stop translation)

how can lipid rafts impact cell signal transduction?

bring PM protein (e.g. receptor) and membrane-associated proteins tg. for more quick and efficient cell signal transduction

what can happen if proteins are localized to lipid rafts

if located within a lipid raft in PM:

• if raft disrupted, the signal transduction cascade involving these proteins are disrupted

• if proteins displaced, no longer any efficient signal transduction cascades involving those proteins

what can happen if proteins are not localized to lipid rafts?

cell signal transduction cascade not impacted by what is happening in the raft

what is the difference between a microdomain and a bulk membrane

microdomain: lipid raft, small and dispersed throughout cell PM

bulk membrane: non-raft region of PM

what components are associated with lipid rafts

• glycosphingolipid (main phospholipid found in bilayer)

• raft-associated protein (receptor)

• cholesterol

• phospholipid

• membrane-associated proteins

how does DHA affect lipid rafts?

DHA has high degree of unsaturation and is sterically incompatible with cholesterol

• disrupts lipid rafts and increases their size → less efficient protein-protein interactions within signalling cascades

• result: less efficient signalling and reduced downstream activation of signalling pathway

describe the structure of DHA and how this can impact lipid rafts

• has 6 double bonds

• free rotation at each double bond (can lead to big awkward structure)

• will spread out and increase size of lipid raft

• proteins spread apart and there is less efficient signalling (in some cases proteins get relocalized)

how does cancer rely on lipid rafts?

• H-RAS and mTOR promote growth of tumor

how does IBD rely on lipid rafts?

• Th17 cells require IL-6 signalling through IL-6R to become activated

• IL-6R localizes to lipid rafts

how does obesity rely on lipid rafts?

• TLR2 and TLR4 localize to lipid rafts

• a(5)B(1) integrin required for NOD recognition of PGN, localizes to lipid rafts

• leptin receptor localizes to lipid rafts

• TNFa receptor and IL-6 receptor localizes to lipid rafts

• disruption of lipid rafts also reduces activation of NFkB and STAT3 (reducing inflammatory mediator production)